• C2C12 cells
• Glucose uptake
• PI3K/Akt pathway
• Skeletal muscle
• Vascular endothelial growth factor B
• bEnd.3 cells

• P01 AG055369 NIA NIH HHS

• Hypoglycemic
• MIN6 cell
• Squash polysaccharides
• Structure
• Type I diabetes

• Animals
• Polysaccharides/pharmacology
• Polysaccharides/chemistry
• Mice
• Diabetes Mellitus, Experimental/drug therapy
• Diabetes Mellitus, Experimental/metabolism
• Insulin/metabolism
• Cell Line
• Hypoglycemic Agents/pharmacology
• Hypoglycemic Agents/chemistry
• Reactive Oxygen Species/metabolism
• Apoptosis/drug effects
• Insulin-Secreting Cells/drug effects
• Insulin-Secreting Cells/metabolism
• Streptozocin

Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs, insulin sensitivity decreases, causing a reduction in insulin secretion and an increase in glucagon secretion. Recently, vascular endothelial growth factor B (VEGFB) has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity. Therefore, we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion, thus contributing to the prevention and cure of prediabetes.

To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.

We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression. Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay, and the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) was determined using western blot. Further, mRNA expression of forkhead box protein O1, phosphoenolpyruvate carboxykinase, and glucose-6 phosphatase was detected via quantitative polymerase chain reaction, and the correlation between the expression of proteins was analyzed via bioinformatics.

In mice with IGT and VEGFB knockout, glucagon secretion increased, and the protein expression of PI3K/AKT decreased dramatically. Further, in mice with VEGFB overexpression, glucagon levels declined, with the activation of the PI3K/AKT signaling pathway.

VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.

• Vascular endothelial growth factor B
• Insulin-mediated
• Glucagon secretion
• Prediabetes
• Impaired glucose tolerance

• Ca2+/CaMK2
• PLCγ/IP3R
• VEGFB
• insulin secretion
• type 2 diabetes mellitus
• β cell

• Animals
• Mice
• Insulin Secretion
• Diabetes Mellitus, Type 2
• Vascular Endothelial Growth Factor B
• Insulin-Secreting Cells
• Signal Transduction
• Craniocerebral Trauma
• Dependovirus/genetics

Nonalcoholic fatty liver disease (NAFLD) refers to fatty liver disease caused by liver injury factors other than alcohol. The disease is characterized by diffuse fat infiltration, including simple steatosis (no inflammatory fat deposition), nonalcoholic fatty hepatitis, liver fibrosis, and so on, which may cause liver cirrhosis, liver failure, and even liver cancer in the later stage of disease progression. At present, the pathogenesis of NAFLD is still being studied. The "two-hit" theory, represented by lipid metabolism disorder and inflammatory reactions, is gradually enriched by the "multiple-hit" theory, which includes multiple factors, such as insulin resistance and adipocyte dysfunction. In recent years, vascular endothelial growth factor B (VEGFB) has been reported to have the potential to regulate lipid metabolism and is expected to become a novel target for ameliorating metabolic diseases, such as obesity and type 2 diabetes. This review summarizes the regulatory role of VEGFB in the onset and development of NAFLD and illustrates its underlying molecular mechanism. In conclusion, the signaling pathway mediated by VEGFB in the liver may provide an innovative approach to the diagnosis and treatment of NAFLD.

• Nonalcoholic fatty liver disease
• Vascular endothelial growth factor B
• "Two-hit" theory
• "Multiple-hit" theory
• Obesity

• VEGF
• adipose tissue
• atherosclerosis
• intestine
• lipid metabolism
• lipoprotein lipase

• apoptosis
• inflammation
• mouse
• oxidative stress
• pancreas injury
• polyunsaturated fatty acid
• streptozotocin

• Mice
• Animals
• Fatty Acids, Omega-3/pharmacology
• Fatty Acids, Omega-3/therapeutic use
• Streptozocin/toxicity
• Fatty Acids, Unsaturated
• Fatty Acids
• Inflammation/drug therapy
• Pancreas
• Dietary Supplements
• Apoptosis
• Oxidative Stress
• Insulins
• Docosahexaenoic Acids/pharmacology
• Eicosapentaenoic Acid/pharmacology

In recent years, studies have demonstrated that vascular endothelial growth factor B (VEGFB) can affect the metabolism of fatty acids and glucose, and it is expected to become a target for the diagnosis and treatment of metabolic diseases such as obesity and diabetes. At present, the specific mechanism that VEGFB regulates lipid and glucose metabolism balance is not completely understood. The present study used systemic VEGFB gene-knockout mice to investigate the effects of downregulation of the VEGFB gene on lipid metabolism and insulin secretion, and to explore the mechanism of the VEGFB pathway involved in the regulation of glucose and lipid metabolism. The morphological changes in the liver and pancreas of mice after VEGFB gene deletion were observed under a light microscope and a scanning electron microscope, and the effects of VEGFB gene deletion on lipid metabolism and blood glucose balance were detected by a serological technique. The detection indexes included total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol. Simultaneously, fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), fasting insulin and glucagon were measured. Insulin sensitivity was assessed by using the insulin tolerance tests and glucose tolerance tests, and function of β-cell islets was evaluated by using the insulin resistance index (HOMA-IR) and pancreatic β-cell secretion index (HOMA-β). Τhe protein expression changes of vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) in mouse islets were detected by western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) after the VEGFB gene was knocked down to analyze the mechanism of VEGFB that may be involved in glucose and lipid metabolism. It was observed that after VEGFB was knocked down, mouse hepatocytes exhibited steatosis and increased secretory vesicles in islet cells. The lipid metabolism indexes such as TG, TC and LDL increased significantly; however, the levels of FBS, postprandial blood glucose and HbA1c decreased, whereas the glucose tolerance increased. Serum insulin secretion increased and HOMA-IR decreased since VEGFB was knocked down. Western blotting and RT-qPCR results revealed that the expression levels of VEGFR1 and neuropilin-1 decreased after the VEGFB gene was knocked down, while the expression levels of VEGFA and VEGFR2 increased. The absence of VEGFB may be involved in the regulation of glucose and lipid metabolism in mice by activating the VEGFA/VEGFR2 signaling pathway. VEGFB is expected to become a new target for the treatment of metabolic diseases such as obesity and diabetes. At present, the mechanism of VEGFB involved in regulating lipid metabolism and glucose metabolism is not completely clear. It was identified that downregulating VEGFB improved lipid metabolism and insulin resistance. The role of VEGFB/VEGFR1 pathway and other family members in regulating glucose and lipid metabolism was detected, which provided a theoretical and experimental basis for VEGFB to affect the regulation of glucose and lipid metabolism balance.

• blood sugar balance
• glucose and lipid metabolism
• insulin resistance
• lipid metabolism
• vascular endothelial growth factor B
• vascular endothelial growth factor receptor 1

It has been demonstrated that vascular endothelial growth factor B (VEGFB) and vascular endothelial growth factor receptor 1 (VEGFR1) play a vital role in regulating vascular biological function. However, the role of VEGFB and VEGFR1 in regulating fat deposition and skeletal muscle growth remains unclear. Therefore, this study was conducted to investigate the effects of VEGFB and VEGFR1 on fat deposition and skeletal muscle growth in mice. Our results showed that knockdown of VEGFB decreased body weight and iWAT index, stimulated the browning of mice iWAT with increased expression of UCP1, decreased the diameters of adipocytes, and elevated energy expenditure. In contrast, knockdown of VEGFB increased gastrocnemius (GAS) muscle index with increased proliferation of GAS muscle by expression of PCNA and Cyclin D1. Meanwhile, knockdown of endothelial VEGFR1 induced the browning of iWAT with increased expression of UCP1 and decreased diameters of adipocytes. By contrast, knockdown of endothelial VEGFR1 inhibited GAS muscle differentiation with decreased expression of MyoD. In conclusion, these results suggested that the loss of VEGFB/VEGFR1 signaling is associated with enhanced browning of inguinal white adipose tissue and skeletal muscle development. These results provided new insights into the regulation of skeletal muscle growth and regeneration, as well as fat deposition, suggesting the potential application of VEGFB/VEGFR1 as an intervention for the restriction of muscle diseases and obesity and related metabolic disorders.

• Adipose Tissue, Brown/metabolism
• Adipose Tissue, White/metabolism
• Animals
• Mice
• Mice, Inbred C57BL
• Muscle Development/genetics
• Muscle, Skeletal/metabolism
• Thermogenesis
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factor B/genetics
• Vascular Endothelial Growth Factor B/metabolism
• Vascular Endothelial Growth Factor Receptor-1/genetics
• Vascular Endothelial Growth Factor Receptor-1/metabolism

• VEGF
• angiogenesis
• atherosclerosis
• cardiovascular diseases
• inflammation

The vascular endothelial growth factor (VEGF) family, the regulator of blood and lymphatic vessels, is mostly investigated in the tumor and ophthalmic field. However, the functions it enjoys can also interfere with the development of atherosclerosis (AS) and further diseases like coronary heart disease (CHD). The source, regulating mechanisms including upregulation and downregulation, target cells/tissues, and known functions about VEGF-A, VEGF-B, VEGF-C, and VEGF-D are covered in the review. VEGF-A can regulate angiogenesis, vascular permeability, and inflammation by binding with VEGFR-1 and VEGFR-2. VEGF-B can regulate angiogenesis, redox, and apoptosis by binding with VEGFR-1. VEGF-C can regulate inflammation, lymphangiogenesis, angiogenesis, apoptosis, and fibrogenesis by binding with VEGFR-2 and VEGFR-3. VEGF-D can regulate lymphangiogenesis, angiogenesis, fibrogenesis, and apoptosis by binding with VEGFR-2 and VEGFR-3. These functions present great potential of applying the VEGF family for treating CHD. For instance, angiogenesis can compensate for hypoxia and ischemia by growing novel blood vessels. Lymphangiogenesis can degrade inflammation by providing exits for accumulated inflammatory cytokines. Anti-apoptosis can protect myocardium from impairment after myocardial infarction (MI). Fibrogenesis can promote myocardial fibrosis after MI to benefit cardiac recovery. In addition, all these factors have been confirmed to keep a link with lipid metabolism, the research about which is still in the early stage and exact mechanisms are relatively obscure. Because few reviews have been published about the summarized role of the VEGF family for treating CHD, the aim of this review article is to present an overview of the available evidence supporting it and give hints for further research.

• VEGF
• angiogenesis
• atherosclerosis
• coronary heart disease
• inflammation
• lipid metabolism
• lymphangiogenesis

Type 2 diabetes (T2D) is characterized by insufficient insulin secretion caused by defective pancreatic β-cell function or insulin resistance, resulting in an increase in blood glucose. However, the mechanism involved in this lack of insulin secretion is unclear. The level of vascular endothelial growth factor B (VEGF-B) is significantly increased in T2D patients. The inactivation of VEGF-B could restore insulin sensitivity in db/db mice by reducing fatty acid accumulation. It is speculated that VEGF-B is related to pancreatic β-cell dysfunction and is an important factor affecting β-cell secretion of insulin. As an in vitro model of normal pancreatic β-cells, the MIN6 cell line can be used to analyze the mechanism of insulin secretion and related biological effects.

To study the role of VEGF-B in the insulin secretion signaling pathway in MIN6 cells and explore the effect of VEGF-B on blood glucose regulation.

The MIN6 mouse pancreatic islet β-cell line was used as the model system. By administering exogenous VEGF-B protein or knocking down VEGF-B expression in MIN6 cells, we examined the effects of VEGF-B on insulin secretion, Ca²⁺ and cyclic adenosine monophosphate (cAMP) levels, and the insulin secretion signaling pathway.

Exogenous VEGF-B inhibited the secretion of insulin and simultaneously reduced the levels of Ca²⁺ and cAMP in MIN6 cells. Exogenous VEGF-B also reduced the expression of phospholipase C gamma 1 (PLCγ1), phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), and other proteins in the insulin secretion pathway. Upon knockdown of VEGF-B, MIN6 cells exhibited increased insulin secretion and Ca²⁺ and cAMP levels and upregulated expression of PLCγ1, PI3K, AKT, and other proteins.

VEGF-B can regulate insulin secretion by modulating the levels of Ca²⁺ and cAMP. VEGF-B involvement in insulin secretion is related to the expression of PLCγ1, PI3K, AKT, and other signaling proteins. These results provide theoretical support and an experimental basis for the study of VEGF-B in the pathogenesis of T2D.

• Type 2 diabetes
• Insulin secretion
• MIN6 cells
• Vascular endothelial growth factor B
• Blood glucose regulation

• AMP-activated protein kinase
• Fatty acid oxidation
• Lipid-lowering
• VEGF-B
• VEGFR1

• blood pressure
• metabolism
• non-alcoholic fatty liver disease
• renal dysfunction
• vascular endothelial growth factor B