Empaglifozin induces changes in the liver metabolome of diabetic rats

Abstract Background Empagliflozin is a potent, highly selective sodium glucose cotransporter-2 (SGLT2) inhibitor used as an effective and well-tolerated antihyperglycaemic agent. Beyond lowering glucose, empagliflozin exerts a favorable effect on a number of nonglycaemic outcomes, including modest reductions in bodyweight and blood pressure, and it has cardioprotective and renoprotective properties in patients with T2D and established cardiovascular disease (EMPA-REG OUTCOME). Purpose Since liver fat content represents a risk factor for cardiovascular diseases, and empagliflozin has been recently suggested to be able to contribute to the early treatment of nonalcoholic fatty liver disease in T2D, we aimed to study the effect of the empagliflozin treatment in the liver metabolome of type 2 diabetic rats. Methods Male ZDF-Leprfa/fa rats were treated with 30 mg/kg/d of empagliflozin p.o for six weeks. Metabolic profiling of the hepatic tissue was analyzed using UHPLC-MS based platforms. We performed a hematoxylin/eosin staining to determine the tissue integrity and liver fat accumulation, and a Masson's trichrome staining to analyze liver fibrosis. All animals were maintained and euthanized following protocols approved by the Animal Care Committee of the University of Santiago de Compostela in accordance with European Union Directive 2010/63. Results Empaglifozin treatment reduced blood glucose levels to normal (128.2±6.51 mg/dL), while untreated control rats showed high glucose levels (404.3±17.49 mg/dL). Hepatic histological analysis did not show differences regarding neither fat accumulation nor fibrosis between empagliflozin treated and control rats. Circulating levels of cholesterol, HDL, LDL, GTP, GGT triglycerides remained unaltered after empaglifozin treatment vs. control. 384 metabolites were analyzed in the liver tissue samples, observing significantly increased levels of 10 types of glycerolipids, 24 phosphatidylcholines, 8 amino acids, 1 polyunsaturated fatty acid, 4 lysophosphatidylethanolamines, 7 lysophosphatidylinositols, 1 carboxylic acid and 1 nucleoside in the empagliflozin treated rats with respect to the control group. In addition, treatment with empagliflozin produced a significant decrease of 1 glycerolipid, 1 phosphatidylcholine, 1 bile acid, 1 nucleoside and the NAD oxidoreduction coenzyme. Conclusions We demonstrated that empagliflozin significantly modify the liver content of the different lipid species, with the most relevant altered metabolic classes belonging to glycerophospholipids, especially monoacyl-species, and aromatic amino acids. Considering the suggested potential beneficial effect of the treatment with empagliflozin in the prevention of liver fibrosis, our metabolomics data can help to evaluate the impact and the mechanism of action of SGLT2 inhibitors at hepatic level. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim

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Chenopodium quinoa Exhibits Antihyperglycemic Activity in Streptozotocin-Induced Diabetic Rats

Cardiovascular & Hematological Agents in Medicinal Chemistry ◽

10.2174/1871525719666210812094837 ◽

2021 ◽

Vol 19 ◽

Author(s):

Amine Azzane ◽

Ayou Amssayef ◽

Mohame Eddouks

Keyword(s):

Antioxidant Activity ◽

Aqueous Extract ◽

Histopathological Examination ◽

Chenopodium Quinoa ◽

Diabetic Rats ◽

Favorable Effect ◽

Antihyperglycemic Activity ◽

Glucose Levels ◽

Blood Glucose Levels

Aims: The aim of the study was to evaluate the antihyperglycemic effect of Chenopodium quinoa. Background: Chenopodium quinoa is a pseudocereal plant with several medicinal properties. Objective: The goal of this investigation was to determine the antihyperglycemic activity of Chenopodium quinoa in both normal and streptozotocin(STZ)-induced diabetic rats. Methods: In this study, the effect of the aqueous extract of Chenopodium quinoa seeds (AECQS) (60 mg/kg) on blood glucose levels was evaluated in both normal and diabetic rats after a single (6 hours) and repeated oral administration (7 days of treatment). The effect of this herb on glucose tolerance and lipid profile was also studied. Additionally, histopathological examination of liver was carried out using the Hematoxylin-Eosin method. Furthermore, the in vitro antioxidant activity as well as a preliminary phytochemical screening and quantification of some secondary metabolites (phenolic compounds, flavonoids and tannins) were performed according to standard methods. Results: AECQS produced a significant lowering effect on plasma glucose levels in STZ-induced diabetic rats. In addition, this extract exhibited a remarkable amelioration on hepatic histopathology in diabetic rats. In addition, the extract exerted a remarkable antioxidant activity which could be due to the presence of some compounds found in this herb. Conclusion: In conclusion, this study demonstrates that the aqueous extract of Chenopodium quinoa seeds has a favorable effect in controlling diabetes mellitus.

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Effects of Exercise Training on Molecular Markers of Lipogenesis and Lipid Partitioning in Fructose-Induced Liver Fat Accumulation

Journal of Nutrition and Metabolism ◽

10.1155/2012/181687 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Siham Yasari ◽

Denis Prud'homme ◽

Frédérique Tesson ◽

Marek Jankowski ◽

Jolanta Gutkowska ◽

...

Keyword(s):

Gene Expression ◽

Exercise Training ◽

Unsaturated Fatty Acids ◽

Regulatory Element ◽

Female Rats ◽

Liver Fat ◽

Standard Diet ◽

Fat Accumulation ◽

High Fructose ◽

The Impact

The present study was designed to investigate the impact of exercise training on lipogenic gene expression in liver and lipid partitioning following the ingestion of a high fructose load. Female rats were exercise-trained for 8 wk or kept sedentary before being submitted to a fasting/refeeding protocol. Rats were further subdivided as follow: rats were fasted for 24 h, refed a standard diet for 24 h, starved for another 24 h, and refed with a standard or a high-fructose diet 24 h before sacrifice. Fructose refeeding was associated with an increase in hepatic lipid content, endocannabinoid receptor 1, sterol regulatory element-binding protein1c, and stearoyl-CoA desaturase1 gene expression in both Sed and TR rats. However, desaturation indexes measured in liver (C16 : 1/C16 : 0 and C18 : 1/C18 : 0) and plasma (C18 : 1/C18 : 0) were higher (P<0.01) in TR than in Sed rats following fructose refeeding. It is concluded that exercise training does not significantly affect fat accumulation and the molecular expression of genes involved in lipogenesis after fasting and fructose refeeding but does modify the partitioning of lipids so as to provide more unsaturated fatty acids in liver without affecting liver fat content.

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The influence of dietary fatty acids on liver fat content and metabolism

Proceedings of The Nutrition Society ◽

10.1017/s0029665119000569 ◽

2019 ◽

Vol 79 (1) ◽

pp. 30-41 ◽

Cited By ~ 12

Author(s):

Leanne Hodson ◽

Fredrik Rosqvist ◽

Siôn A Parry

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Dietary Fat ◽

Fat Content ◽

Dietary Fatty Acids ◽

Liver Fat ◽

Liver Fat Content ◽

Alcoholic Fatty Liver ◽

Fat Accumulation ◽

The Impact

Non-alcoholic fatty liver disease encompasses a spectrum of conditions from hepatic steatosis through to cirrhosis; obesity is a known risk factor. The liver plays a major role in regulating fatty acid metabolism and perturbations in intrahepatic processes have potential to impact on metabolic health. It remains unclear why intra-hepatocellular fat starts to accumulate, but it likely involves an imbalance between fatty acid delivery to the liver, fatty acid synthesis and oxidation within the liver and TAG export from the liver. As man spends the majority of the day in a postprandial rather than postabsorptive state, dietary fatty acid intake should be taken into consideration when investigating why intra-hepatic fat starts to accumulate. This review will discuss the impact of the quantity and quality of dietary fatty acids on liver fat accumulation and metabolism, along with some of the potential mechanisms involved. Studies investigating the role of dietary fat in liver fat accumulation, although surprisingly limited, have clearly demonstrated that it is total energy intake, rather than fat intake per se, that is a key mediator of liver fat content; hyperenergetic diets increase liver fat whilst hypoenergetic diets decrease liver fat content irrespective of total fat content. Moreover, there is now, albeit limited evidence emerging to suggest the composition of dietary fat may also play a role in liver fat accumulation, with diets enriched in saturated fat appearing to increase liver fat content to a greater extent when compared with diets enriched in unsaturated fats.

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Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00058.2011 ◽

2011 ◽

Vol 301 (3) ◽

pp. R668-R673 ◽

Cited By ~ 28

Author(s):

Rami Abu Fanne ◽

Taher Nassar ◽

Samuel N. Heyman ◽

Nuha Hijazi ◽

Abd Al-Roof Higazi

Keyword(s):

Amino Acids ◽

Neuroprotective Effect ◽

Artery Occlusion ◽

Diabetic Rats ◽

Metabolic Effects ◽

Therapeutic Window ◽

Neuroprotective Effects ◽

Glucose Levels ◽

Cerebral Artery Occlusion

In patients with acute ischemic stroke, diabetes and hyperglycemia are associated with increased infarct size, more profound neurologic deficits and higher mortality. Notwithstanding extensive clinical and experimental data, treatment of stroke-associated hyperglycemia with insulin is controversial. In addition to hyperglycemia, diabetes and even early prediabetic insulin resistance are associated with increased levels of amino acids, including the neurotoxic glutamate, in the circulation. The pleiotropic metabolic effects of insulin include a reduction in the concentration of amino acids in the circulation. In this article, we show that in diabetic rats exposed to transient middle cerebral artery occlusion, a decrease of plasma glutamate by insulin or glucagon reduces CSF glutamate, improves brain histology, and preserves neurologic function. The neuroprotective effect of insulin and glucagon was similar, notwithstanding their opposite effects on blood glucose. The therapeutic window of both hormones overlapped with the short duration (∼30 min) of elevated brain glutamate following brain trauma in rodents. Similar neuroprotective effects were found after administration of the glutamate scavenger oxaloacetate, which does not affect glucose metabolism. These data indicate that insulin and glucagon exert a neuroprotective effect within a very brief therapeutic window that correlates with their capacity to reduce glutamate, rather than by modifying glucose levels.

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Abstract 003: The Impact of MHCII Loss in Myeloid Cells and Adipocytes on Atherosclerosis and Liver Fat Accumulation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.38.suppl_1.003 ◽

2018 ◽

Vol 38 (Suppl_1) ◽

Author(s):

Alecia Blaszczak ◽

Valerie Wright ◽

Joey Liu ◽

Tuo Deng ◽

David Bradley ◽

...

Keyword(s):

Myeloid Cells ◽

Liver Fat ◽

Fat Accumulation ◽

The Impact

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Potential of karamunting (Rhodomyrtus tomentosa) fraction against kidney damage in diabetic rats

Herba Polonica ◽

10.2478/hepo-2021-0010 ◽

2021 ◽

Vol 67 (2) ◽

pp. 9-16

Author(s):

Mgs Irsan Saleh ◽

Rachmat Hidayat ◽

Geri Febriyanto ◽

Nita Parisa

Keyword(s):

Diabetes Mellitus ◽

Blood Glucose ◽

Diabetic Rats ◽

Kidney Damage ◽

Male Rats ◽

Native Plant ◽

Glucose Levels ◽

Blood Glucose Levels ◽

The Impact ◽

Rhodomyrtus Tomentosa

Summary Introduction: Karamunting (Rhodomyrtus tomentosa) is Indonesian native plant that contains high anti-oxidant compounds with the potential to suppress oxidative stress activity in cells. This study is the first research to specifically explore the role of the karamunting fraction in protecting kidney damage due to the formation of AGEs in the renal glomerulus in diabetes mellitus. Objective: This study aims to assess the impact of karamunting on blood glucose profile, HbA1c, insulin profile and kidney condition (AGEs expression, TNF-α and kidney histology) in diabetic rats. Methods: The karamunting extraction process was carried out by maceration with ethanol. Induction of diabetes mellitus was carried out using streptozotocin. Thirty male rats (Rattus norvegicus), Wistar strain weighing between 200–250 grams were the subject in this study. HbA1c, insulin, TNF-α, AGEs levels were evaluated in the kidney tissue. Histological assessment of the kidney was carried out. Results: Karamunting can improve blood glucose levels in diabetic rats. This improvement in blood glucose levels causes an improvement in the level of HbA1c. Administration of karamunting fraction can prevent AGEs deposition in renal tissue, which in turn will inhibits the inflammation and prevents further damage of kidneys. Conclusion: Karamunting fraction can improve blood glucose regulation so that it can prevent further damage and complications of kidney organs in diabetic rats.

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Pharmacological effects of novel microvesicles of basil, on blood glucose and the lipid profile: a preclinical study

Scientific Reports ◽

10.1038/s41598-021-01713-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Branislava Teofilovic ◽

Svetlana Golocorbin-Kon ◽

Nebojsa Stilinovic ◽

Nevena Grujic-Letic ◽

Aleksandar Raškovic ◽

...

Keyword(s):

Blood Glucose ◽

Blood Glucose Concentration ◽

Day Treatment ◽

Release Kinetics ◽

Water Extract ◽

Preclinical Study ◽

Diabetic Rats ◽

Pharmacological Effects ◽

Glucose Levels ◽

The Impact

AbstractMicroencapsulation represents a process that can create targeted, controlled release kinetics of drugs, thus optimizing therapeutic efficacy. Our group has investigated the impact of this technology on Wistar rats to determine pharmacological efficacy of basil extracts. Animals were treated with water extract of Ocimum basilicum in microvesicles and with combination of basil extracts and 3α,7α-dihydroxy-12-keto-5-cholanate, also known as 12-monoketocholic acid (MKC) acid in microvesicles for 7 days. Alloxan was used to induce hyperglycemia. Pharmacological effects on glycemia were evaluated by measuring blood glucose levels in alloxan-induced diabetic rats. Microvesicles were prepared using the Büchi-based microencapsulating system developed in our lab. The dose of basil extract that was orally administered in rats was 200 mg/kg and the dose of MKC acid was 4 mg/kg as per established protocols. A seven-day treatment with basil aqueous extract, as well as a combination of basil and MKC acid extract in the pharmaceutical formulation, led to a statistically significant reduction in the blood glucose concentration of animals with alloxan-induced hyperglycemia compared to pre-treatment values (p < 0.05 and p < 0.01), which indicates that basil has hypoglycemic and antihyperglycemic effects. Microvesicles, as a pharmaceutical-technological formulation, substantially enhance the hypolipidemic action of basil extract with MKC acid.

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Gentiana kurroo Royle attenuates the metabolic aberrations in diabetic rats; Swertiamarin, swertisin and lupeol being the possible bioactive principles

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2017-0002 ◽

2017 ◽

Vol 14 (3) ◽

Cited By ~ 3

Author(s):

Khalid Ghazanfar ◽

Khan Mubashir ◽

Showkat A Dar ◽

Tazeen Nazir ◽

Iqra Hameed ◽

...

Keyword(s):

Diabetic Control ◽

Serum Glucose ◽

Diabetic Rats ◽

Antidiabetic Activity ◽

Oral Glucose ◽

Western Himalayas ◽

Reference Drug ◽

Glucose Levels ◽

The Impact ◽

Serum Glutamate

AbstractBackgroundRoyle is a medicinally important plant of north-western Himalayas used for various ailments. In the present study, the plant extracts were investigated for the antidiabetic effects in streptozotocin-induced diabetic rats.MethodsThe impact of the extracts on serum glucose levels of diabetic rats was compared with reference drug – glibenclamide-treated diabetic rats. Streptozotocin injection was used to induce diabetes in fasted rats. Various biochemical, physiological and histopathological parameters in diabetic rats were observed for assessing the antidiabetic activity.ResultsThe serum glucose concentrations in diabetic rats were significantly lowered by the extracts (methanolic and hydroethanolic at the doses of 250 and 500 mg/kg body weight). Several related biochemical parameters like creatinine, low-density lipoproteins, triglycerides, cholesterol, alkaline phosphatase, serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase were likewise decreased by the concentrates. The extracts also showed reduction in feed and water consumption of diabetic rats when compared with the diabetic control. The extracts were found to demonstrate regenerative/protective effect on β-cells of pancreas in diabetic rats. The methanolic and hydroethanolic extracts also exhibited hypoglycaemic effect in normal glucose-fed rats (oral glucose tolerance tests). LC-MS characterization of this extract showed the presence of these compounds – Swertiamarin, swertisin, lupeol, etc.ConclusionsThe current study demonstrated the counter diabetic capability of

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Hydrogen Cyanide Polymers from the Impact of Comet P/Shoemaker-Levy 9 on Jupiter

International Astronomical Union Colloquium ◽

10.1017/s025292110001469x ◽

1997 ◽

Vol 161 ◽

pp. 179-187

Author(s):

Clifford N. Matthews ◽

Rose A. Pesce-Rodriguez ◽

Shirley A. Liebman

Keyword(s):

Amino Acids ◽

Solar System ◽

Hydrogen Cyanide ◽

Nitrogen Heterocycles ◽

Laboratory Studies ◽

Heterogeneous Solids ◽

The Many ◽

Comet Halley ◽

The Impact ◽

By Products

AbstractHydrogen cyanide polymers – heterogeneous solids ranging in color from yellow to orange to brown to black – may be among the organic macromolecules most readily formed within the Solar System. The non-volatile black crust of comet Halley, for example, as well as the extensive orangebrown streaks in the atmosphere of Jupiter, might consist largely of such polymers synthesized from HCN formed by photolysis of methane and ammonia, the color observed depending on the concentration of HCN involved. Laboratory studies of these ubiquitous compounds point to the presence of polyamidine structures synthesized directly from hydrogen cyanide. These would be converted by water to polypeptides which can be further hydrolyzed to α-amino acids. Black polymers and multimers with conjugated ladder structures derived from HCN could also be formed and might well be the source of the many nitrogen heterocycles, adenine included, observed after pyrolysis. The dark brown color arising from the impacts of comet P/Shoemaker-Levy 9 on Jupiter might therefore be mainly caused by the presence of HCN polymers, whether originally present, deposited by the impactor or synthesized directly from HCN. Spectroscopic detection of these predicted macromolecules and their hydrolytic and pyrolytic by-products would strengthen significantly the hypothesis that cyanide polymerization is a preferred pathway for prebiotic and extraterrestrial chemistry.

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