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Abstract: Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L-cells in response to nutrients. GLP-1 lowers blood glucose levels by stimulating insulin secretion from pancreatic beta-cells in a glucose-dependent manner. In addition, GLP-1 slows gastric emptying, suppresses appetite, reduces plasma glucagon, and stimulates glucose disposal, which are beneficial for glucose homeostasis. Therefore, incretin-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase IV, an enzyme which inactivates GLP-1, have been developed for treatment of diabetes. This review outlines our knowledge of the actions of GLP-1 on insulin secretion and biosynthesis, beta-cell proliferation and regeneration, and protection against beta-cell damage, as well as the involvement of recently discovered signaling pathways of GLP-1 action, mainly focusing on pancreatic beta-cells. [Copyright &y& Elsevier]

Highlights: [•] We fabricated transparent indium-tin oxide electrodes (ITO) coated by parylene-C. [•] Adipose tissue-derived stem cells (ADSCs) were cultured on ITO electrode-based chip. [•] Impedance of ADSCs was affected by the age-related size and proliferation of cells. [•] Impedance measurement-based detection of the senescence of stem cells is possible. [ABSTRACT FROM AUTHOR]

Abstract: For stem cell-based tissue engineering or tissue therapy, control of the quality of isolated stem cells is required. In this study, we used the electrical impedance spectroscopy to characterize the effect of passage on the morphological change and the proliferative capacity of adipose tissue-derived stem cells (ADSCs) during cell growth on the transparent ITO electrodes. ADSCs adhered to the ITO electrode and proliferated during cell growth. The phase contrast image of ADSCs on the electrode showed that the cells at passage 9 had a small and spindle-shaped morphology while the cells at passage 31 were flattened and larger than younger cells. The real part of the impedances of passage 9 cells were lower than passage 31 at the beginning time of culture due to the larger size of older cells adhered to the electrode. Then, the values of passage 9 cells were increased and distinguishable from passage 31 due the higher proliferation rate of younger cells. The experimental results showed that the impedance measurement could characterize the age-related morphological change and the proliferative capacity of ADSCs during cell growth. [Copyright &y& Elsevier]

Type 1 diabetes results from the loss of insulin-producing pancreatic β cells following the action of β-cell-specific autoimmune responses. One possible treatment for type 1 diabetes is the development of β-cell substitutes by introducing an insulin-producing gene into non-β cells, which would evade the β-cell-specific autoimmune attack. However, this approach has been hampered by the absence of (1) an appropriate glucose-sensing system to regulate insulin gene transcription; (2) enzymes that process proinsulin to insulin; and (3) glucose-regulatable exocytosis in the target cells. Recent attempts to solve these problems have sought new methods for effective gene transfer and have addressed issues such as the expression and release of insulin in response to the physiological stimulus of glucose, the production of biologically active insulin, and the selection of an ideal target cell for the expression of the insulin gene. [ABSTRACT FROM AUTHOR]

COVID-19, caused by the novel coronavirus SARS-CoV-2, is an abbreviated name for coronavirus disease 2019. COVID-19 became a global pandemic in early 2020. It predominantly affects not only the upper and lower respiratory tract, but also multiple organs, including the kidney, heart, and brain. The mortality of COVID-19 patients is high in men and in elderly patients with age-related diseases such as hypertension and diabetes. The angiotensin converting enzyme-2 (ACE-2), a component in the renin-angiotensin-aldosterone system (RAAS), plays as cell surface receptors for SARS-CoV-2. A recent study proved that coronavirus SARS-CoV-2 also uses dipeptidyl peptidase-4 (DPP4, also known as adenosine deaminase complexing protein 2, CD26) as a co-receptor when entering cells. In addition, DPP4 is also implicated in the regulation of the immune response. Thus, the combination of DPP4 inhibition and suppression of ACE-2/RAAS may be a novel therapeutic strategy for combating this pandemic. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Psoralea corylifolia L. seed (PCS) is a traditional medicine effective against various diseases. In this study, we aimed to investigate the effect of bavachin, the major active component of PCS, on DN in db/db mice. Bavachin (10 mg/kg/day) was administered orally to 12-week-old male db/db mice for 6 wk. For in vitro experiments, SV40 MES13 cells were treated with bavachin in the presence of 25 mM glucose. Food and water intake and urine mass were significantly increased in db/db mice compared to wild-type CON mice, but bavachin administration significantly reduced these increases. Urinary microalbumin, blood urea nitrogen, and creatinine clearance which were significantly increased in db/db mice, were also decreased by bavachin administration. Glomerular area and collagen deposition in the kidney were significantly decreased in db/db mice following bavachin administration. Increased renal levels of fibrotic factors, fibronectin, COL1A1, and α-SMA, were reduced following bavachin administration. Protein expressions of antioxidant enzymes, namely SOD2, catalase, and HO-1, and mitochondrial function-related factors, namely SIRT1, PGC1α, Nrf1, and mtTFA, were reduced in the kidney tissues of db/db mice compared to wild-type CON mice, and bavachin administration upregulated these protein expressions. In vitro studies also showed that bavachin decreases mitochondria ROS production, increases the expression of PGC-1α and SIRT1, and decreases the expression of α-SMA in high glucose-treated SV40 MES13 cells. Based on these results, bavachin improved DN by inhibiting oxidative stress and enhancing mitochondrial function. [ABSTRACT FROM AUTHOR]

The production of reactive oxygen species (ROS) increases with aging and is associated with liver diseases. ChREBP is involved in lipogenic gene expression in hepatocytes, and we hypothesized that increases in ROS production would induce liver metabolic diseases via regulation of ChREBP expression. Mechanism studies were conducted using H 2 O 2 induced HepG2 cells and primary hepatocytes from old mouse. We detected increases in ChREBP expression, lipogenic gene (FAS and SCD1) expression, and intracellular triglyceride (TG) levels in H 2 O 2 -treated HepG2 cells, which were inhibited by ChREBP knockdown. ChREBP expression and intracellular TG levels were higher in primary hepatocytes from old mice than in those of young mice. Compared with old wild-type mice, intracellular TG levels were significantly reduced in primary hepatocytes from old ChREBP knockout mice. Furthermore, H 2 O 2 stimulation was found to induce HNF-4α expression in HepG2 cells and this expression was higher in primary hepatocytes from old mice. ChIP-qPCR assays indicated that binding of HNF-4α to ChREBP promoter was significantly increased by H 2 O 2 treatment in HepG2 cells. Further study revealed that H 2 O 2 -promoted increases in ChREBP expression and intracellular TG levels were significantly inhibited by HNF-4α knockdown. H 2 O 2 treatment also significantly increased ASK1 expression, whereas ASK1 knockdown inhibited H 2 O 2 -induced HNF-4α expression. Collectively, our data indicate that an increase in ROS production can induce HNF-4α expression via the ASK1 pathway and subsequently enhances the expression of ChREBP, thereby contributing to lipogenesis. This pathway may be involved in the elevated liver lipid levels associated with aging and oxidative stress. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Design and synthesis of novel GCGR antagonists as pyrimidine derivatives. • The compound of (R) -7a decreased the glucagon-induced cAMP production. • The compound of (R) -7a decreased the glucagon-induced glucose production. • The compound of (R) -7a decreased the glucagon-induced glucose excursion in vivo. • The compound of (R) -7a lowering fasting blood glucose levels in db / db mice. Abstract The hormone glucagon increases blood glucose levels through increasing hepatic glucose output. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, the inhibition of glucagon receptor is one target for the treatment of hyperglycemia in type 2 diabetes. Here we designed and synthesized a series of small molecules based on phenylpyrimidine. Of these, the compound (R) -7a most significantly decreased the glucagon-induced cAMP production and glucagon-induced glucose production during in vitro and in vivo assays. In addition, (R) -7a showed good efficacy in glucagon challenge tests and lowered blood glucose levels in diabetic db/db mice. Our results suggest that the compound (R) -7a could be a potential glucose-lowering agent for treating type 2 diabetes. [ABSTRACT FROM AUTHOR]

Liquiritigenin (LQ) is a major active component of licorice root, which is a flavone used for treating many diseases, including diabetes. LQ has been shown to exhibit a glucose-lowering effect in diabetic mice. Therefore, we investigated the potential of LQ to protect against lipotoxicity-induced beta-cell apoptosis and the underlying molecular mechanisms. Exposure of INS-1 rat insulinoma cells to LQ significantly increased cell viability and blocked palmitate (PA)-induced apoptosis, as evidenced by the reduction of Annexin-V-stained cells, cleaved caspase-3 levels, and poly (ADP-ribose) polymerase (PARP) activity, as well as upregulation of Bcl-2 expression. Moreover, LQ treatment significantly reduced the endoplasmic reticulum (ER) stress response by reducing phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK), phosphorylated eIF-2a, and CHOP expression in PA-treated INS-1 cells. The anti-apoptotic effect of LQ treatment was reversed through co-treatment with fulvestrant, a specific inhibitor of the estrogen receptor. LQ also increased AKT phosphorylation, and inactivation of this molecular event failed to decrease PERK phosphorylation with LQ treatment in PA-treated INS-1 cells. This effect was further accompanied by an inability to recover cell viability. These results suggest that LQ protects INS-1 cells from lipotoxicity-induced apoptosis by suppressing ER stress. We conclude that estrogen receptor-mediated AKT phosphorylation is one of the mechanisms contributing to the anti-apoptotic effect of LQ. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease and lysophosphatidic acid (LPA) has recently been reported to contribute to its pathogenesis through keratinocyte proliferation. In this study, we investigated the metabolic changes in the LPA-induced keratinocyte hyperproliferation and underlying mechanisms. HaCaT or HEKa cells were treated with LPA in the presence or absence of various chemical inhibitors. The glycolysis stress was measured using the Seahorse extracellular flux analyzer. Gene knockdown by siRNA transfection was used to investigate the role of LPAR1, PGAM1, and HIF-1α in LPA-induced metabolic changes. We confirmed the expression of PGAM1 and HIF-1α in imiquimod (IMQ)-induced psoriasis-like BALB/c mice. LPA increased aerobic glycolysis; however, treatment with ki16425, or LPAR1 knockdown inhibited LPA-induced glycolysis in HaCaT cells. LPA increased the expression of glycolytic enzyme PGAM1 through LPAR1. PGAM1 knockdown in HaCaT cells suppressed LPA-induced cell proliferation, changes in cell cycle factor expression, and inhibited LPA-induced aerobic glycolysis. LPA sequentially activated AKT, mTOR, its downstream target, p70 S6K, and increased HIF-1α expression through LPAR1. HIF-1α knockdown inhibited LPA-induced PGAM1 expression and aerobic glycolysis. A6730 also decreased LPA-induced activation of mTOR and p70 S6K and LPA-induced increases in HIF-1α and PGAM1 expression. Ki16425 suppressed the increased expression of PGAM1 and HIF-1α in the lesions of IMQ-induced psoriasis-like mice. In primary keratinocytes, LPA/LPAR1 signaling also induced AKT-mediated aerobic glycolysis. Collectively, the results demonstrated that LPA induces aerobic glycolysis via AKT/mTOR/HIF-1α-dependent PGAM1 expression during keratinocytes proliferation and this might be one of the mechanisms of psoriasis development. [ABSTRACT FROM AUTHOR]

Disuse muscle atrophy is characterized by a decrease in muscle mass and strength and an increase in glycolytic muscle fiber type. Although Schisandra chinensis extract has beneficial effects on muscle atrophy induced by various conditions (e.g., dexamethasone and aging), the effect of gomisin G, a lignan component of S. chinensis , on disuse muscle atrophy is unclear. Here, we induced disuse muscle atrophy through wire immobilization of the hind legs in mice followed by the oral administration of gomisin G. The cross-sectional area and muscle strength in disuse muscle atrophic mice were increased by gomisin G; however, the total muscle mass did not increase. Gomisin G decreased the expression of muscle atrophic factors (myostatin, atrogin-1, and MuRF1) but increased the expression of protein synthesis factors (mTOR and 4E-BP1). In H 2 O 2 -treated C2C12 myotubes, the level of puromycin incorporation (as a marker of protein synthesis) gradually increased in a dose-dependent manner by gomisin G. Furthermore, gomisin G induced a muscle fiber switch from fast-type glycolytic fibers (type 2B) to slow-type oxidative fibers (type I, 2A) in the gastrocnemius (GA) muscle as proved a decrease in the expression of TnI-FS and an increase in the expression of TnI-SS. Gomisin G increased mitochondrial DNA content and ATP levels in the GA muscle and COX activity in H 2 O 2 -treated C2C12 myotubes, improving mitochondrial function. Mechanistically, mitochondrial biogenesis is regulated by gomisin G via the Sirt 1/PGC-1α signaling pathway, targeting NRF1 and TFAM. These data suggest that gomisin G has a potential therapeutic effect on disuse muscle atrophy. [Display omitted] • Gomisin G improves grip strength in disuse muscle atrophic mice. • Gomisin G increases muscle synthesis rate in H2O2-treated C2C12 myotubes. • Gomisin G increases slow-type oxidative fiber contents in muscle of disuse mice. • Gomisin G induces mitochondrial biogenesis via the Sirt 1/PGC-1α signaling pathway. [ABSTRACT FROM AUTHOR]

11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) has been targeted for new drugs to treat type 2 diabetes and metabolic syndrome. In this study, we determined whether the inhibition of 11βHSD1 with a new selective inhibitor, SKI2852, could improve lipid profiles, glucose levels, and insulin sensitivity in type 2 diabetic and obese conditions. SKI2852 showed a potent inhibition of cortisone to cortisol conversion for over 80% in both liver and adipose tissue ex vivo from orally administered C57BL/6 mice, and in vivo analysis results were consistent with this. Repeated oral administrations of SKI2852 in diet-induced obesity (DIO) and ob / ob mice revealed a partially beneficial effect of SKI2852 in improving levels of cholesterols, triglycerides, free fatty acids, postprandial glucose, and/or blood hemoglobinA 1c . SKI2852 significantly reduced body weight increase in ob / ob mice, and efficiently suppressed hepatic mRNA levels of gluconeogenic enzymes in DIO mice. Moreover, SKI2852 enhanced hepatic and whole body insulin sensitivities in hyperinsulinemic-euglycemic clamp experiment in DIO mice. In conclusion, these results indicate that selective and potent inhibition of 11βHSD1 by SKI2852, thus blockade of active glucocorticoid conversion, may improve many aspects of metabolic parameters in type 2 diabetes and metabolic diseases, mainly by inhibitions of hepatic gluconeogenesis and partial improvements of lipid profiles. Our study strongly support that SKI2852 may have a great potential as a novel candidate drug for the treatment of diabetes and metabolic diseases. [ABSTRACT FROM AUTHOR]

Abstract: Aging-dependent physiological conditions are attributed to parenchymal structural changes to cellular functions in aged organisms. Compared to the young animals, the primary hepatocytes from old rats showed a higher glucose output and a higher expression of the key gluconeogenesis-regulating enzyme, phosphoenol pyruvate carboxykinase (PEPCK). The primary hepatocytes from old rats showed a higher glucose output and a higher expression of the key gluconeogenesis-regulating enzyme, phosphoenol pyruvate carboxykinase (PEPCK), compared with those from the young animals. The in situ hybridization study showed increased PEPCK mRNA expression in the aged liver tissues. The livers from old rats showed loosened hexagonal hepatic lobular structures, increased collagen accumulation, and high expression of the hypoxia marker hypoxia-inducible factor 1α (HIF1α). Hypoxia increased the PEPCK mRNA and protein expression levels in accordance with the HIF1α expression. PEPCK promoter luciferase reporter assay showed that hypoxia increased PEPCK through transcriptional activation. Furthermore, the hepatocyte nuclear factor α (HNF4α) protein, but not the HNF4α mRNA level, increased in parallel with the PEPCK mRNA expression under hypoxic conditions. Glucose production increased under hypoxic conditions, but this increment diminished by HNF4α siRNA in young hepatocytes. Moreover, increased glucose production from old rat hepatocytes was reversed by the down-regulation of HNF4α through a specific siRNA. This study suggests that the mild hypoxic conditions in response to aging-dependent hepatic structural changes may contribute to the induction of the gluconeogenic enzyme PEPCK through HNF4α protein stabilization. [Copyright &y& Elsevier]

An abstract of the article "Glucose-Dependent Insulin Production by Liver-Specific, Glucose-Regulatable Synthetic Promoters Results in the Cure of Diabetes," by Jaeseok Han, Brienne McLane, Hee-Sook Jun and Ji-Won Yoon is presented.