Wenyi Li

Glucose-mediated repression of menin promotes pancreatic β-cell proliferation.

Menin, encoded by the Men1 gene, is responsible for β-cell tumor formation in patients with multiple endocrine neoplasia type 1. Recently, menin has been proven to negatively regulate β-cell proliferation during pregnancy. However, it is unclear whether menin is involved in pancreatic β-cell proliferation in response to other physiological replication stimuli, such as glucose. In this study, we found that the menin level was significantly reduced in high glucose-treated INS1 cells and primary rat islets, both with increased proliferation. A similar observation was found in islets isolated from rats subjected to 72-h continuous glucose infusion. The glucose-induced proliferation was inhibited by menin overexpression. Further molecular studies showed that glucose-induced menin suppression was blocked by PI3K/Akt pathway inhibitors. A major PI3K/Akt substrate, Foxo1, was shown to enhance menin transcription levels by binding the promoter region of the Men1 gene. Therefore, we conclude that glucose inhibits menin expression via the PI3K/Akt/Foxo1 pathway and hence promotes pancreatic β-cell proliferation. Our study suggests that menin might serve as an important intracellular target of glucose to mediate the mitogenic effect that glucose exerts in pancreatic β-cells.

Differentially expressed genes in Men1 knockout and wild‑type embryoid bodies for pancreatic islet development

The Men1 gene has been identified as the gene responsible for MEN-1, a hereditary syndrome transmitted as an autosomal dominant trait. Disruption of the Men1 gene results in defects in the development of multiple organs, including pancreatic islets. Homozygous disruption of Men1 in mice causes embryonic lethality, making it difficult to determine the genes involved in defects of pancreatic islets during embryonic development. In this study, embryoid bodies formed from null mutant (Men1-/-) and wild-type (Men1+/+) embryonic stem cells were used as a model system to investigate the effects of the Men1 gene on pancreatic islet development. Using RT-PCR, SOX17, FOXA2 and NKX2.2 were found to be differentially expressed between the two embryoid bodies. Additionally, the gene expression profile of these Men1-/- embryoid bodies was characterized in detail by DNA microarray techniques, and a series of putative menin-targeted genes was identified. Our study suggests a critical role for Men1 in pancreatic islet development, and indicates that genes such as SOX17, FOXA2, NKX2.2 and SOX4 are potential targets of Men1.

Raptor regulates functional maturation of murine beta cells

Diabetes is associated with beta cell mass loss and islet dysfunctions. mTORC1 regulates beta cell survival, proliferation and function in physiological and pathological conditions, such as pregnancy and pancreatectomy. Here we show that deletion of Raptor, which is an essential component of mTORC1, in insulin-expressing cells promotes hypoinsulinemia and glucose intolerance. Raptor-deficient beta cells display reduced glucose responsiveness and exhibit a glucose metabolic profile resembling fetal beta cells. Knockout islets have decreased expression of key factors of functional maturation and upregulation of neonatal markers and beta cell disallowed genes, resulting in loss of functional maturity. Mechanistically, Raptor-deficient beta cells show reduced expression of DNA-methyltransferase 3a and altered patterns of DNA methylation at loci that are involved in the repression of disallowed genes. The present findings highlight a novel role of mTORC1 as a core mechanism governing postnatal beta cell maturation and physiologic beta cell mass during adulthood.

Liraglutide protects pancreatic beta cells during an early intervention in Gato-Kakizaki rats.

Glucagon‐like peptide‐1 (GLP‐1) analogues have emerged as insulin secretagogues and are widely used in type 2 diabetic patients. GLP‐1 analogues also demonstrate a promotion of beta cell proliferation and reduction of apoptosis in rodents. In the present study, we investigated the protection of pancreatic beta cells by early use (at the age of 2 weeks) of GLP‐1 analogue, liraglutide in Gato‐Kakizaki (GK) rats and explored the underlying mechanisms.

Liraglutide protects pancreatic beta cells during an early intervention in Gato-Kakizaki rats (Gato-Kakizaki大鼠使用利拉鲁肽进行早期干预可以保护胰腺β细胞)

Glucagon‐like peptide‐1 (GLP‐1) analogues have emerged as insulin secretagogues and are widely used in type 2 diabetic patients. GLP‐1 analogues also demonstrate a promotion of beta cell proliferation and reduction of apoptosis in rodents. In the present study, we investigated the protection of pancreatic beta cells by early use (at the age of 2 weeks) of GLP‐1 analogue, liraglutide in Gato‐Kakizaki (GK) rats and explored the underlying mechanisms.

Sfrp5 mediates glucose-induced proliferation in rat pancreatic β-cells

The cellular and molecular mechanisms of glucose-stimulated β-cell proliferation are poorly understood. Recently, secreted frizzled-related protein 5 (encoded by Sfrp5; a Wnt signaling inhibitor) has been demonstrated to be involved in β-cell proliferation in obesity. A previous study demonstrated that glucose enhanced Wnt signaling to promote cell proliferation. We hypothesized that inhibition of SFRP5 contributes to glucose-stimulated β-cell proliferation. In this study, we found that the Sfrp5 level was significantly reduced in high glucose-treated INS-1 cells, primary rat β-cells, and islets isolated from glucose-infused rats. Overexpression of SFRP5 diminished glucose-stimulated proliferation in both INS-1 cells and primary β-cells, with a concomitant inhibition of the Wnt signaling pathway and decreased cyclin D2 expression. In addition, we showed that glucose-induced Sfrp5 suppression was modulated by the PI3K/AKT pathway. Therefore, we conclude that glucose inhibits Sfrp5 expression via the PI3K/AKT pathway and hence promotes rat pancreatic β-cell proliferation.

How radical cations react? - Distonic radical cation mediated α(nucleophilic), β(radical)-dibenzoloxylation of donor ArCH = CHR

Rate determination and product studies have disclosed that the fragmentation pattern of radical cations 2-propenyl-1,4-dimethoxybenzene (1+ ·) and 2-propenyl-1,4,5-trimethoxybenzene (2+·) generated in one-electron oxidation of their parent substrates by 4-nitrobenzoyl peroxide (3) in CH3CN is greatly affected by ring-substitution status of the donor molecules. While ringbenzoloxylation (product 5) predominated in the reaction of dimethoxylated substrate (1), the oxidation of trimethoxylated donor 2 ended up with distonic radical cation mediated α,β-di-4-nitrobenzoloxylation as the major pathway.

Reactivity and reaction pathways of alkylalkoxybenzene radical cations. Part 3. Effects of 2-alkyl substituents on the relative importance of ring-substitution over deprotonation of 2-alkyl-1,4-dimethoxybenzene radical cations

One-electron oxidation of 2-alkyl-1,4-dimethoxybenzenes 1a-f (2-alkyl=Me, Et, i-Pr, cy-C3H5CH2, PhCH2 and t-Bu) by 4-nitrobenzoyl peroxide 2 and pentaflurobenzoyl peroxide 3 was proved by the observation of great acceleration of decomposition of the peroxides at room temperature, the detection of the corresponding radical cations 1+• a-f and product analysis. The product studies have disclosed that under the conditions employed (in acetonitrile at 40°C), the reaction pathways of the radical cations are greatly dependent on the nature of 2-alkyl substituents: Ring-4-nitrobenzoloxylation product at C5 and C6 were obtained exclusively in the reactions of the donors with aliphatic 2-alkyl substituents bearing at least one α-hydrogen atom, such as 1a, 1b, 1c and 1d; whereas in the case of 1e (with 2-benzyl group), both ring-substitution at C5 (4e) and C6 (5e) and deprotonation/4-nitrobenzoloxylation products 8e were isolated; from the donor without α-hydrogen atom, 1f, de-t-butylation products 12 and t-butyl 4-nitrobenzoate 13 were incorporated with ring-substitution at C5 (4f) and C6 (5f). Furthermore, the product distribution (4 over 5) is also affected by the bulkiness of 2-alkyl group. For all the electron-transfer reactions, large amounts of the benzoic acid (4-NO2-C6H4COOH or C6F5COOH) were generated and trace amounts of de-methylation product (2-alkyl-1,4-benzoqinones 6) were also detected by 1H NMR.

Liraglutide protects pancreatic beta cells during an early intervention in Gato-Kakizaki rats (Gato-Kakizaki大鼠使用利拉鲁肽进行早期干预可以保护胰腺β细胞): Liraglutide protects pancreatic beta cells in rats

Glucagon‐like peptide‐1 (GLP‐1) analogues have emerged as insulin secretagogues and are widely used in type 2 diabetic patients. GLP‐1 analogues also demonstrate a promotion of beta cell proliferation and reduction of apoptosis in rodents. In the present study, we investigated the protection of pancreatic beta cells by early use (at the age of 2 weeks) of GLP‐1 analogue, liraglutide in Gato‐Kakizaki (GK) rats and explored the underlying mechanisms.