Protective effect of 4,6-O-ethylidene glucose against the cytotoxicity of streptozotocin in pancreatic β cells in vivo: indirect evidence for the presence of a glucose transporter in β cells

ABSTRACT Ethylidene glucose (4,6-O-ethylidene glucose; EG) is known to bind the outer surface of the glucose transporter in the membranes of human erythrocytes and other mammalian cells. If a glucose transport system is present on pancreatic β cells and recognizes the glucose moiety of streptozotocin (STZ), EG should protect β cells from the cytotoxicity of STZ when it is administered with STZ. This possibility was examined in in-vivo experiments in rats. When EG and STZ were injected into rats together the animals did not become diabetic, as judged by (1) their blood glucose levels, (2) response in a glucose-tolerance test, and (3) insulin secretion in response to feeding. These results suggest that there is a glucose transporter present in β cells and also the transport of streptozotocin into β cells through this system. J. Endocr. (1987) 112, 375–378

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Gpr1 is an active chemerin receptor influencing glucose homeostasis in obese mice

Journal of Endocrinology ◽

10.1530/joe-14-0069 ◽

2014 ◽

Vol 222 (2) ◽

pp. 201-215 ◽

Cited By ~ 52

Author(s):

Jillian L Rourke ◽

Shanmugam Muruganandan ◽

Helen J Dranse ◽

Nichole M McMullen ◽

Christopher J Sinal

Keyword(s):

Adipose Tissue ◽

Glucose Homeostasis ◽

Stromal Vascular Fraction ◽

Tolerance Test ◽

Glucose Levels ◽

Brown Adipose ◽

Elevated Glucose ◽

And Function ◽

G Protein Coupled

Chemerin is an adipose-derived signaling protein (adipokine) that regulates adipocyte differentiation and function, immune function, metabolism, and glucose homeostasis through activation of chemokine-like receptor 1 (CMKLR1). A second chemerin receptor, G protein-coupled receptor 1 (GPR1) in mammals, binds chemerin with an affinity similar to CMKLR1; however, the function of GPR1 in mammals is essentially unknown. Herein, we report that expression of murineGpr1mRNA is high in brown adipose tissue and white adipose tissue (WAT) and skeletal muscle. In contrast to chemerin (Rarres2) andCmklr1,Gpr1expression predominates in the non-adipocyte stromal vascular fraction of WAT. Heterozygous and homozygousGpr1-knockout mice fed on a high-fat diet developed more severe glucose intolerance than WT mice despite having no difference in body weight, adiposity, or energy expenditure. Moreover, mice lackingGpr1exhibited reduced glucose-stimulated insulin levels and elevated glucose levels in a pyruvate tolerance test. This study is the first, to our knowledge, to report the effects ofGpr1deficiency on adiposity, energy balance, and glucose homeostasisin vivo. Moreover, these novel results demonstrate that GPR1 is an active chemerin receptor that contributes to the regulation of glucose homeostasis during obesity.

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Dietary (-)-epicatechin mitigates high fat-induced apoptosis, oxidative and endoplasmic reticulum stress in pancreatic β-cells both in vivo and in vitro

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2020.12.383 ◽

2021 ◽

Vol 165 ◽

pp. 44

Author(s):

Eleonora Cremonini ◽

Maëlys Rouget ◽

Solenne Arredi ◽

Charlotte Devulder-Mercier ◽

Robin Cellier ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

High Fat ◽

Β Cells ◽

Pancreatic Β Cells ◽

Induced Apoptosis

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Activity of Indenoisoquinolines against African Trypanosomes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00650-07 ◽

2008 ◽

Vol 53 (1) ◽

pp. 123-128 ◽

Cited By ~ 11

Author(s):

Rahul P. Bakshi ◽

Dongpei Sang ◽

Andrew Morrell ◽

Mark Cushman ◽

Theresa A. Shapiro

Keyword(s):

Anticancer Agents ◽

Mammalian Cells ◽

Sleeping Sickness ◽

Water Soluble ◽

African Trypanosomes ◽

In Vivo Experiments ◽

Topoisomerase Ib ◽

Topoisomerase Poisons

ABSTRACT African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.

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Teucrium polium: Potential Drug Source for Type 2 Diabetes Mellitus

Biology ◽

10.3390/biology11010128 ◽

2022 ◽

Vol 11 (1) ◽

pp. 128

Author(s):

Yaser Albadr ◽

Andrew Crowe ◽

Rima Caccetta

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Secretion ◽

Β Cells ◽

Pancreatic Β Cells ◽

Glucose Levels ◽

Teucrium Polium

The prevalence of type 2 diabetes mellitus is rising globally and this disease is proposed to be the next pandemic after COVID-19. Although the cause of type 2 diabetes mellitus is unknown, it is believed to involve a complex array of genetic defects that affect metabolic pathways which eventually lead to hyperglycaemia. This hyperglycaemia arises from an inability of the insulin-sensitive cells to sufficiently respond to the secreted insulin, which eventually results in the inadequate secretion of insulin from pancreatic β-cells. Several treatments, utilising a variety of mechanisms, are available for type 2 diabetes mellitus. However, more medications are needed to assist with the optimal management of the different stages of the disease in patients of varying ages with the diverse combinations of other medications co-administered. Throughout modern history, some lead constituents from ancient medicinal plants have been investigated extensively and helped in developing synthetic antidiabetic drugs, such as metformin. Teucrium polium L. (Tp) is a herb that has a folk reputation for its antidiabetic potential. Previous studies indicate that Tp extracts significantly decrease blood glucose levels r and induce insulin secretion from pancreatic β-cells in vitro. Nonetheless, the constituent/s responsible for this action have not yet been elucidated. The effects appear to be, at least in part, attributable to the presence of selected flavonoids (apigenin, quercetin, and rutin). This review aims to examine the reported glucose-lowering effect of the herb, with a keen focus on insulin secretion, specifically related to type 2 diabetes mellitus. An analysis of the contribution of the key constituent flavonoids of Tp extracts will also be discussed.

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Maintaining a Physiological Blood Glucose Level with ‘Glucolevel’, a Combination of Four Anti-Diabetes Plants Used in the Traditional Arab Herbal Medicine

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nem047 ◽

2008 ◽

Vol 5 (4) ◽

pp. 421-428 ◽

Cited By ~ 57

Author(s):

Omar Said ◽

Stephen Fulder ◽

Khaled Khalil ◽

Hassan Azaizeh ◽

Eli Kassis ◽

...

Keyword(s):

Juglans Regia ◽

Human Fibroblasts ◽

Tolerance Test ◽

Positive Control ◽

Diabetic Rats ◽

Yeast Cells ◽

Sugar Uptake ◽

Glucose Levels

Safety and anti-diabetic effects of Glucolevel, a mixture of dry extract of leaves of theJuglans regiaL,Olea europeaL,Urtica dioicaL andAtriplex halimusL were evaluated usingin vivoandin vitrotest systems. No sign of toxic effects (using LDH assay) were seen in cultured human fibroblasts treated with increasing concentrations of Glucolevel. Similar observations were seenin vivostudies using rats (LD50: 25 g/kg). Anti-diabetic effects were evidenced by the augmentation of glucose uptake by yeast cells (2-folds higher) and by inhibition of glucose intestinal absorption (∼49%) in a rat gut-segment. Furthermore, treatment with Glucolevel of Streptozotocin-induced diabetic rats for 2–3 weeks showed a significant reduction in glucose levels [above 400 ± 50 mg/dl to 210 ± 22 mg/dl (P< 0.001)] and significantly improved sugar uptake during the glucose tolerance test, compared with positive control. In addition, glucose levels were tested in sixteen human volunteers, with the recent onset of type 2 diabetes mellitus, who received Glucolevel tablets 1 × 3 daily for a period of 4 weeks. Within the first week of Glucolevel consumption, baseline glucose levels were significantly reduced from 290 ± 40 to 210 ± 20 mg/dl. At baseline, a subgroup of eleven of these subjects had glucose levels below 300 mg% and the other subgroup had levels ≥ 300 mg%. Clinically acceptable glucose levels were achieved during the 2–3 weeks of therapy in the former subgroup and during the 4th week of therapy in the latter subgroup. No side effect was reported. In addition, a significant reduction in hemoglobin A1C values (8.2 ± 1.03 to 6.9 ± 0.94) was found in six patients treated with Glucolevel. Results demonstrate safety, tolerability and efficacy of herbal combinations of four plants that seem to act differently but synergistically to regulate glucose-homeostasis.

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Abstract 606: Impaired Glucose Metabolism in the Triggering Receptor Expressed in Myeloid Cells Like Transcript- 1 Null Mice A Link to Obesity

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.606 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Elizabeth Castro Rivera ◽

Abdías Díaz Rosado ◽

Anthony V Washington

Keyword(s):

Serum Insulin ◽

Insulin Response ◽

Myeloid Cells ◽

Tolerance Test ◽

Similar Response ◽

Fatty Acid Production ◽

Glucose Levels ◽

Significant Difference

Fat rich foods have been shown to produce increased body weight and diabetes in various strains of mice. When fed ad libitum with a high fat diet (HFD), apolipoprotein E deficient ( apoe -/- ) mice develop hypercholesterolemia, but are not known to be obese. Our laboratory demonstrated that the triggering receptor expressed in myeloid cells (TREM) like transcript-1 (TLT-1), as a potential target for intervention during atherosclerosis, diabetes, and obesity. Crossing the treml1 -/- mouse onto an apoe -/- background (DKO), we found DKO mice had smaller lesions than apoe -/- mice, yet had significantly higher triglycerides and weight gain over a 20-week period of HFD. Further investigation demonstrated treml1 -/- mice to have higher cholesterol than wild type mice (wt), suggesting the treml1 mutation contributes to the phenotype observed in DKO mice. Glucose evaluation of treml1 -/- , treml1 +/- and wt mice, showed a significant difference in basal glucose, and in plasma glucose clearance, as revealed by intraperitoneal (IP) glucose tolerance test. Analysis of serum insulin by ELISA showed no differences, while IP insulin tolerance test revealed treml1 -/- and treml1 +/- mice present apparent insulin hypersensitivity, as represented by the steady glucose decline 15 min post injection, with no recovery after two hours. Western blot performed in various tissues, demonstrated the presence of a TLT-1 splice variant that lacks the extracellular domain (TLT-1s), in the adipose tissue of treml1 -/- but not wt mice. Analysis of insulin response, in vivo by insulin sensitivity assay and in vitro using TSA 201 cells transfected with TLT-1s to determine the effect on AKT activation, revealed enhanced phosphorylation in the presence of TLT-1, with a similar response observed in vitro. This data support a model where TLT-1s modulation of AKT phosphorylation, increases adipocyte glucose uptake, leading to: low blood glucose levels, increased fatty acid production and storage, and the obese phenotype we observed in our mice.

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Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia

10.2337/figshare.16797871 ◽

2021 ◽

Author(s):

Xingjing Liu ◽

Peng Sun ◽

Qingzhao Yuan ◽

Jinyang Xie ◽

Ting Xiao ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Chow Diet ◽

Β Cells ◽

Pancreatic Β Cells ◽

Calcium Calmodulin Dependent ◽

Normal Chow

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The present study revealed a new in vivo role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the Cask gene in mouse β-cells (βCASKKO), and the glucose metabolism was evaluated in <a>βCASKKO</a> mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared to HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-βCASKKO mice. These results indicated that knockout of the Cask gene in β cells had a diverse effect on glucose homeostasis: reduced insulin secretion in ND-fed mice, but improves insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

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Treatment With Naringenin Elevates the Activity of Transcription Factor Nrf2 to Protect Pancreatic β-Cells From Streptozotocin-Induced Diabetes in vitro and in vivo

Frontiers in Pharmacology ◽

10.3389/fphar.2018.01562 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 12

Author(s):

Rashmi Rajappa ◽

Dornadula Sireesh ◽

Magesh B. Salai ◽

Kunka M. Ramkumar ◽

Suryanarayanan Sarvajayakesavulu ◽

...

Keyword(s):

Transcription Factor ◽

Β Cells ◽

Pancreatic Β Cells ◽

Streptozotocin Induced Diabetes

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Protein Kinase CK2 Controls CaV2.1-Dependent Calcium Currents and Insulin Release in Pancreatic β-cells

International Journal of Molecular Sciences ◽

10.3390/ijms21134668 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4668

Author(s):

Rebecca Scheuer ◽

Stephan Ernst Philipp ◽

Alexander Becker ◽

Lisa Nalbach ◽

Emmanuel Ampofo ◽

...

Keyword(s):

Insulin Secretion ◽

Calcium Currents ◽

Insulin Biosynthesis ◽

Β Cells ◽

Pancreatic Β Cells ◽

Voltage Dependent ◽

Regulatory Impact ◽

Kinase Ck2

The regulation of insulin biosynthesis and secretion in pancreatic β-cells is essential for glucose homeostasis in humans. Previous findings point to the highly conserved, ubiquitously expressed serine/threonine kinase CK2 as having a negative regulatory impact on this regulation. In the cell culture model of rat pancreatic β-cells INS-1, insulin secretion is enhanced after CK2 inhibition. This enhancement is preceded by a rise in the cytosolic Ca2+ concentration. Here, we identified the serine residues S2362 and S2364 of the voltage-dependent calcium channel CaV2.1 as targets of CK2 phosphorylation. Furthermore, co-immunoprecipitation experiments revealed that CaV2.1 binds to CK2 in vitro and in vivo. CaV2.1 knockdown experiments showed that the increase in the intracellular Ca2+ concentration, followed by an enhanced insulin secretion upon CK2 inhibition, is due to a Ca2+ influx through CaV2.1 channels. In summary, our results point to a modulating role of CK2 in the CaV2.1-mediated exocytosis of insulin.

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