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Population pharmacodynamic modeling of exenatide after 2-week treatment in STZ/NA diabetic rats.

ABSTRACT: The purpose of this study is to investigate the effect of exenatide on glycemic control following two administration routes in a streptozotocin/nicotinamide (STZ/NA)-induced diabetic rat model, and to develop a pharmacodynamic model to better understand the disease progression and the action of exenatide in this experimental system. Two groups of STZ/NA-induced diabetic rats were treated for 2 weeks with 20 (?g/kg/day) of exenatide, either by continuous subcutaneous (SC) infusion or two SC injections daily. Disease progression was associated with slower glucose utilization. Fasting blood glucose was significantly reduced by 30 mg/dL in both treatment groups at the end of 2 weeks. A subsequent intravenous glucose tolerance test (IVGTT) confirmed an improved glucose tolerance in both treatment groups; however, overall glycemic control was similar between groups, likely due to the relatively low and short-term drug exposure. A population indirect response model was successfully developed to simultaneously describe the STZ/NA-induced disease progression, responses to an IVGTT, and exenatide effects on these systemic challenges. The unified model includes a single set of parameters, and the cumulative area under the drug-receptor concentration curve was used as a unique driving force to account for systemic effects long after drug elimination.

SUBMITTER: Chen T

PROVIDER: S-EPMC3808969 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Population pharmacodynamic modeling of exenatide after 2-week treatment in STZ/NA diabetic rats.

Chen Ting T Kagan Leonid L Mager Donald E DE

Journal of pharmaceutical sciences 20130729 10

The purpose of this study is to investigate the effect of exenatide on glycemic control following two administration routes in a streptozotocin/nicotinamide (STZ/NA)-induced diabetic rat model, and to develop a pharmacodynamic model to better understand the disease progression and the action of exenatide in this experimental system. Two groups of STZ/NA-induced diabetic rats were treated for 2 weeks with 20 (μg/kg/day) of exenatide, either by continuous subcutaneous (SC) infusion or two SC injec ...[more]

PMID: 23897494

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Project description:BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) are commonly used in the management of type 2 diabetes mellitus (T2DM) and have been found to worsen the reduction of skeletal muscle mass in individuals with T2DM. This study aims to examine the potential of exercise in mitigating the skeletal muscle atrophy induced by SGLT2i treatment.MethodsA rat model of T2DM (40 male Sprague-Dawley rats; T2DM induced by a combination of high-fat diet and streptozotocin) was used to examine the effects of six-week treatment with Dapagliflozin (DAPA, SGLT2i) in combination with either aerobic exercise (AE) or resistance training (RT) on skeletal muscle. T2DM-eligible rats were randomized into the T2DM control group (CON, n = 6), DAPA treatment group (DAPA, n = 6), DAPA combined with aerobic exercise intervention group (DAPA + AE, n = 6), and DAPA combined with resistance training intervention group (DAPA + RT, n = 6). To assess the morphological changes in skeletal muscle, myosin ATPase and HE staining were performed. mRNA expression levels of Atrogin-1, MuRF1, and Myostatin were determined using quantitative PCR. Furthermore, protein expression levels of AKT, p70S6K, mTOR, FoXO1/3A, NF-κB, and MuRF1 were examined through western blotting.ResultsBoth the administration of DAPA alone and the combined exercise intervention with DAPA resulted in significant reductions in blood glucose levels and body weight in rats. However, DAPA alone administration led to a decrease in skeletal muscle mass, whereas RT significantly increased skeletal muscle mass and muscle fiber cross-sectional area. The DAPA + RT group exhibited notable increases in both total protein levels and phosphorylation levels of AKT and p70S6K in skeletal muscle. Moreover, the DAPA, DAPA + AE, and DAPA + RT groups demonstrated downregulation of protein expression (FoXO1/3A) and mRNA levels (Atrogin-1, MuRF1, and Myostatin) associated with muscle atrophy.ConclusionsOur findings provide support for the notion that dapagliflozin may induce skeletal muscle atrophy through mechanisms unrelated to protein metabolism impairment in skeletal muscle, as it does not hinder protein metabolic pathways while reduces muscle atrophy-related genes. Additionally, our observations reveal that RT proves more effective than AE in enhancing skeletal muscle mass and muscle fiber cross-sectional area in rats with T2DM by stimulating protein anabolism within the skeletal muscle.

Project description:This study aimed to assess the renopreventive effect of enalapril and/or paricalcitol on streptozotocin (STZ) diabetes-induced nephropathy and to elucidate their mechanisms of action through investigation of the effects on renal oxidative stress, antioxidant defense system and expressions of TNF-α, p53, caspase-3, and Bcl-2. Diabetes mellitus was induced in fasting male Wistar rats by single intraperitoneal injection of STZ (45 mg /kg b.w.) dissolved in citrate buffer (pH 4.5). Ten days after STZ injection, the diabetic rats were treated with enalapril (25 mg/l of drinking water) and/or paricalcitol (8 μg/kg b.w. per os) dissolved in 5% DMSO daily for 4 weeks. The obtained data revealed that the treatment of diabetic Wistar rats with enalapril and/or paricalcitol led to significant decreases in the elevated serum urea, uric acid, creatinine, sodium and potassium levels; thereby reflecting the improvement of the impaired kidney function. The deteriorated kidney lipid peroxidation, GSH content and GST and catalase activities in diabetic rats were significantly ameliorated as a result of treatment with enalapril and/or paricalcitol. The elevated fasting and post-prandial serum glucose levels and the lowered serum insulin and C-peptide levels were also improved. The treatment with enalapril and paricalcitol in combination was the most potent in decreasing the elevated serum glucose levels. Moreover, the treatment of diabetic rats successfully prevented the diabetes-induced histopathological deleterious changes of kidney and islets of Langerhans of pancreas. In association, the immunohistochemically detected pro-inflammatory cytokine, TNF-α, and apoptotic mediators, p53 and caspase-3, were remarkably decreased in kidney of diabetic rats as a result of treatment while the expression of anti-apoptotic protein Bcl-2 was increased. Based on these findings, it can be concluded that enalapril and paricalcitol alone or in combination can prevent STZ diabetes-induced nephropathy through amelioration of the glycemic state and antioxidant defense system together with the suppression of oxidative stress, inflammation and apoptosis. However, the treatment of diabetic rats with enalapril and paricalcitol in combination has no further significant improvement effects on renal function and damage when compared with enalapril or paclitaxel treated diabetic groups.

Project description:Diabetes in the elderly increases cognitive impairment, but the underlying mechanisms are still far from fully understood. A non-targeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) was performed to screen out the serum biomarkers of diabetic mild cognitive impairment (DMMCI) in rats. Total 48 SD rats were divided into three groups, Normal control (NC) group, high-fat diet (HFD) fed group and type 2 diabetes mellitus (T2DM) group. The T2DM rat model was induced by intraperitoneal administration of streptozotocin (STZ, 35 mg/kg) after 6 weeks of high-fat diet (HFD) feeding. Then each group was further divided into 4-week and 8-week subgroups, which were calculated from the time point of T2DM rat model establishment. The novel object recognition test (NORT) and the Morris water maze (MWM) method were used to evaluate the cognitive deficits in all groups. Compared to the NC-8w and HFD-8w groups, both NOR and MWM tests indicated significant cognitive dysfunction in the T2DM-8w group, which could be used as an animal model of DMMCI. Serum was ultimately collected from the inferior vena cava after laparotomy. Metabolic profiling analysis was conducted using ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) technology. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to verify the stability of the model. According to variable importance in the project (VIP > 1) and the p-value of t-test (P < 0.05) obtained by the OPLS-DA model, the metabolites with significant differences were screened out as potential biomarkers. In total, we identified 94 differentially expressed (44 up-regulated and 50 down-regulated) endogenous metabolites. The 10 top up-regulated and 10 top down-regulated potential biomarkers were screened according to the FDR significance. These biomarkers by pathway topology analysis were primarily involved in the metabolism of sphingolipid (SP) metabolism, tryptophan (Trp) metabolism, Glycerophospholipid (GP) metabolism, etc. Besides, SP metabolism, Trp metabolism and GP metabolism mainly belonging to the lipid metabolism showed marked perturbations over DMMCI and may contribute to the development of disease. Taken collectively, our results revealed that T2DM could cause cognitive impairment by affecting a variety of metabolic pathways especially lipid metabolism. Besides, serum PE, PC, L-Trp, and S1P may be used as the most critical biomarkers for the early diagnosis of DMMCI.

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Population pharmacodynamic modeling of exenatide after 2-week treatment in STZ/NA diabetic rats.

Publications

Population pharmacodynamic modeling of exenatide after 2-week treatment in STZ/NA diabetic rats.

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