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Liraglutide improves pancreatic Beta cell mass and function in alloxan-induced diabetic mice.

ABSTRACT: Glucagon-like peptide-1 (GLP-1) receptor agonists potentiate glucose-induced insulin secretion. In addition, they have been reported to increase pancreatic beta cell mass in diabetic rodents. However, the precise mode of action of GLP-1 receptor agonists still needs to be elucidated. Here we clarify the effects of the human GLP-1 analog liraglutide on beta cell fate and function by using an inducible Cre/loxP-based pancreatic beta cell tracing system and alloxan-induced diabetic mice. Liraglutide was subcutaneously administered once daily for 30 days. The changes in beta cell mass were examined as well as glucose tolerance and insulin secretion. We found that chronic liraglutide treatment improved glucose tolerance and insulin response to oral glucose load. Thirty-day treatment with liraglutide resulted in a 2-fold higher mass of pancreatic beta cells than that in vehicle group. Liraglutide increased proliferation rate of pancreatic beta cells and prevented beta cells from apoptotic cells death. However, the relative abundance of YFP-labeled beta cells to total beta cells was no different before and after liraglutide treatment, suggesting no or little contribution of neogenesis to the increase in beta cell mass. Liraglutide reduced oxidative stress in pancreatic islet cells of alloxan-induced diabetic mice. Furthermore, the beneficial effects of liraglutide in these mice were maintained two weeks after drug withdrawal. In conclusion, chronic liraglutide treatment improves hyperglycemia by ameliorating beta cell mass and function in alloxan-induced diabetic mice.

SUBMITTER: Tamura K

PROVIDER: S-EPMC4418765 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Liraglutide improves pancreatic Beta cell mass and function in alloxan-induced diabetic mice.

Tamura Kanako K Minami Kohtaro K Kudo Maya M Iemoto Keisuke K Takahashi Harumi H Seino Susumu S

PloS one 20150504 5

Glucagon-like peptide-1 (GLP-1) receptor agonists potentiate glucose-induced insulin secretion. In addition, they have been reported to increase pancreatic beta cell mass in diabetic rodents. However, the precise mode of action of GLP-1 receptor agonists still needs to be elucidated. Here we clarify the effects of the human GLP-1 analog liraglutide on beta cell fate and function by using an inducible Cre/loxP-based pancreatic beta cell tracing system and alloxan-induced diabetic mice. Liraglutid ...[more]

PMID: 25938469

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Project description:One week of treatment with EGF and gastrin (EGF/G) was shown to restore normoglycemia and to induce islet regeneration in mice treated with the diabetogenic agent alloxan. The mechanisms underlying this regeneration are not fully understood. We performed genetic lineage tracing experiments to evaluate the contribution of beta cell neogenesis in this model. One day after alloxan administration, mice received EGF/G treatment for one week. The treatment could not prevent the initial alloxan-induced beta cell mass destruction, however it did reverse glycemia to control levels within one day, suggesting improved peripheral glucose uptake. In vitro experiments with C2C12 cell line showed that EGF could stimulate glucose uptake with an efficacy comparable to that of insulin. Subsequently, EGF/G treatment stimulated a 3-fold increase in beta cell mass, which was partially driven by neogenesis and beta cell proliferation as assessed by beta cell lineage tracing and BrdU-labeling experiments, respectively. Acinar cell lineage tracing failed to show an important contribution of acinar cells to the newly formed beta cells. No appearance of transitional cells co-expressing insulin and glucagon, a hallmark for alpha-to-beta cell conversion, was found, suggesting that alpha cells did not significantly contribute to the regeneration. An important fraction of the beta cells significantly lost insulin positivity after alloxan administration, which was restored to normal after one week of EGF/G treatment. Alloxan-only mice showed more pronounced beta cell neogenesis and proliferation, even though beta cell mass remained significantly depleted, suggesting ongoing beta cell death in that group. After one week, macrophage infiltration was significantly reduced in EGF/G-treated group compared to the alloxan-only group. Our results suggest that EGF/G-induced beta cell regeneration in alloxan-diabetic mice is driven by beta cell neogenesis, proliferation and recovery of insulin. The glucose-lowering effect of the treatment might play an important role in the regeneration process.

Project description:The cJun N-terminal Kinases (JNK) emerged as a major link between obesity and insulin resistance, but their role in the loss of pancreatic β-cell mass and function driving the progression from insulin resistance to type-2 diabetes and in the complications of diabetes was not investigated to the same extent. Furthermore, it was shown that pan-JNK inhibition exacerbates kidney damage in the db/db model of obesity-driven diabetes. Here we investigate the role of JNK1 in the db/db model of obesity-driven type-2 diabetes. Mice with systemic ablation of JNK1 (JNK1-/-) were backcrossed for more than 10 generations in db/+ C57BL/KS mice to generate db/db-JNK1-/- mice and db/db control mice. To define the role of JNK1 in the loss of β-cell mass and function occurring during obesity-driven diabetes we performed comprehensive metabolic phenotyping, evaluated steatosis and metabolic inflammation, performed morphometric and cellular composition analysis of pancreatic islets, and evaluated kidney function in db/db-JNK1-/- mice and db/db controls. db/db-JNK1-/- mice and db/db control mice developed insulin resistance, fatty liver, and metabolic inflammation to a similar extent. However, db/db-JNK1-/- mice displayed better glucose tolerance and improved insulin levels during glucose tolerance test, higher pancreatic insulin content, and larger pancreatic islets with more β-cells than db/db mice. Finally, albuminuria, kidney histopathology, kidney inflammation and oxidative stress in db/db-JNK1-/- mice and in db/db mice were similar. Our data indicate that selective JNK1 ablation improves glucose tolerance in db/db mice by reducing the loss of functional β-cells occurring in the db/db mouse model of obesity-driven diabetes, without significantly affecting metabolic inflammation, steatosis, and insulin sensitivity. Furthermore, we have found that, differently from what previously reported for pan-JNK inhibitors, selective JNK1 ablation does not exacerbate kidney dysfunction in db/db mice. We conclude that selective JNK1 inactivation may have a superior therapeutic index than pan-JNK inhibition in obesity-driven diabetes.

Project description:IntroductionDespite the development of oral hypoglycemic medications, diabetes and its associated complications continue to be significant clinical issues. The purpose of this study was to examine the antidiabetic effects of Vigna radiata (L.) Wilczek seeds in mice that had been given alloxan to cause diabetes.MethodsIn Swiss albino mice, diabetes was brought on by a single intraperitoneal injection of the drug alloxan (150 mg/kg). For 14 days, glibenclamide (5 mg/kg) and methanol extract of V. radiata seeds (100, 200, and 400 mg/kg) were given orally. Following oral administration of V. radiata to mice, the blood glucose levels (BGL) and body weight were measured at 7 and 14 days. The mice were sacrificed at the end of the trial, and blood samples were taken for the evaluation of insulin, glycated hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), high-density lipoprotein (HDL), total cholesterol (TC), and triglyceride (TG) levels. It was determined how much glycogen was present in the liver. Additionally, the total phenolic and flavonoid contents of V. radiata were determined, along with the in vitro DPPH (2, 2 diphenyl-1-picrylhrazyl) free radical-scavenging activity. P < 0.05 was chosen as the cutoff for statistical significance.ResultsFollowing oral administration of V. radiata for 14 days, diabetic mice's BGL and bad cholesterol (TC and TG) levels significantly decreased, while HDL levels increased. Treatment with V. radiata significantly decreased the levels of AST, ALT, and glycated hemoglobin when compared with diabetes control. On the other hand, it raised insulin levels and the amount of liver glycogen. V. radiata underwent phytochemical analysis, which identified the presence of tannins, saponins, phenols, alkaloids, terpenoids, steroids, flavonoids, and glycosides. Per gram of V. radiata seed extract, the total phenolic content was 43.12 ± 3.14 mg of gallic acid equivalents, while the total flavonoid content was 38.35 ± 2.6 mg of quercetin equivalents. Ascorbic acid was shown to have an IC50 value of 18.64 µg/ml during a DPPH-scavenging assay, while V. radiata had an IC50 value of 73.35 µg/ml.ConclusionAccording to the findings of the current study, the methanolic extract of the seeds from the plant V. radiata possesses significant antidiabetic characteristics that are on par with those of the commonly used drug glibenclamide. Hence, V. radiata seems to be effective as a natural antidiabetic.

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Liraglutide improves pancreatic Beta cell mass and function in alloxan-induced diabetic mice.

Publications

Liraglutide improves pancreatic Beta cell mass and function in alloxan-induced diabetic mice.

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