Inhibitory effects of type 2 diabetes serum components in P450 inhibition assays can potential diagnose asymptomatic diabetic mice

ABSTRACT Human diabetics frequently suffer delayed wound healing, increased susceptibility to localized and systemic infections, and limb amputations as a consequence of the disease. Lower-limb infections in diabetic patients are most often polymicrobial, involving mixtures of aerobic, facultative anaerobic, and anaerobic bacteria. The purpose of this study is to determine if these organisms contribute to synergy in polymicrobial infections by using diabetic mice as an in vivo model. The model was the obese diabetic mouse strain BKS.Cg-m +/+ Lepr db /J, a model of human type 2 diabetes. Young (5- to 6-week-old) prediabetic mice and aged (23- to 24-week-old) diabetic mice were compared. The mice were injected subcutaneously with mixed cultures containing Escherichia coli, Bacteroides fragilis, and Clostridium perfringens. Progression of the infection (usually abscess formation) was monitored by examining mice for bacterial populations and numbers of white blood cells at 1, 8, and 22 days postinfection. Synergy in the mixed infections was defined as a statistically significant increase in the number of bacteria at the site of injection when coinfected with a second bacterium, compared to when the bacterium was inoculated alone. E. coli provided strong synergy to B. fragilis but not to C. perfringens. C. perfringens and B. fragilis provided moderate synergy to each other but only in young mice. B. fragilis was anergistic (antagonistic) to E. coli in coinfections in young mice at 22 days postinfection. When age-matched nondiabetic mice (C57BLKS/J) were used as controls, the diabetic mice exhibited 5 to 35 times the number of CFU as did the nondiabetic mice, indicating that diabetes was a significant factor in the severity of the polymicrobial infections.

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Disparate Effects of Metformin on Mycobacterium tuberculosis Infection in Diabetic and Nondiabetic Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01422-20 ◽

2020 ◽

Vol 65 (1) ◽

pp. e01422-20

Author(s):

Harindra D. Sathkumara ◽

Karyna Hansen ◽

Socorro Miranda-Hernandez ◽

Brenda Govan ◽

Catherine M. Rush ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mycobacterium Tuberculosis ◽

Disease Burden ◽

Low Dose ◽

Diabetic Mice ◽

Antidiabetic Drug ◽

Mycobacterium Tuberculosis Infection ◽

Therapeutic Concentration ◽

Content Type

ABSTRACTComorbid type 2 diabetes poses a great challenge to the global control of tuberculosis. Here, we assessed the efficacy of metformin (MET), an antidiabetic drug, in mice infected with a very low dose of Mycobacterium tuberculosis. In contrast to diabetic mice, infected nondiabetic mice that received the same therapeutic concentration of MET presented with significantly higher disease burden. This warrants further studies to investigate the disparate efficacy of MET against tuberculosis in diabetic and nondiabetic individuals.

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Reduction of Insulin Signaling Upregulates Angiopoietin-like Protein 4 Through Elevated Free Fatty Acids in Diabetic Mice

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0031-1291258 ◽

2011 ◽

Vol 120 (03) ◽

pp. 139-144 ◽

Cited By ~ 16

Author(s):

N. Mizutani ◽

N. Ozaki ◽

Y. Seino ◽

A. Fukami ◽

E. Sakamoto ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fatty Acids ◽

Adipose Tissue ◽

Mrna Expression ◽

High Fat Diet ◽

Serum Triglyceride ◽

Diabetic Mice ◽

Brown Adipose

AbstractAngiopoietin-like protein 4 (Angptl4) is thought to cause an increase in serum triglyceride levels. In the present study, we elucidated Angptl4 expression in the mouse models of type 1 and type 2 diabetes mellitus, and investigated the possible mechanisms involved.Type 1 diabetes was induced in C57BL/6 J mice by treating them with streptozotocin (STZ). Type 2 diabetes was induced by feeding the mice a high-fat diet (HFD) for 18 weeks.The levels of Angptl4 mRNA expression in liver, white adipose tissue (WAT), and brown adipose tissue (BAT) were found to increase in the STZ diabetic mice relative to control mice. This effect was attenuated by insulin administration. In the HFD diabetic mice, the Angptl4 mRNA expression levels were increased in liver, WAT, and BAT. Treatment with metformin for 4 weeks attenuated the increased levels of Angptl4 mRNA. Fatty acids (FAs) such as palmitate and linoleate induced Angptl4 mRNA expression in H4IIE hepatoma cells and 3T3-L1 adipocytes. Treatment with insulin but not metformin attenuated FA-induced Angptl4 mRNA expression in H4IIE. Both insulin and metformin did not influence the effect of FAs in 3T3-L1 cells.These observations demonstrated that Angptl4 mRNA expression was increased through the elevated free FAs in diabetic mice.

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MiR-27b augments bone marrow progenitor cell survival via suppressing the mitochondrial apoptotic pathway in Type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00073.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. E391-E401 ◽

Cited By ~ 9

Author(s):

Hainan Li ◽

Jenny Liu ◽

Yihan Wang ◽

Zhiyao Fu ◽

Maik Hüttemann ◽

...

Keyword(s):

Type 2 Diabetes ◽

Bone Marrow ◽

Cell Therapy ◽

Progenitor Cell ◽

Diabetic Mice ◽

Tissue Repair And Regeneration ◽

Autologous Cell ◽

Autologous Cell Therapy ◽

Type 2 Diabetic

Bone marrow-derived progenitor cells (BMPCs) are potential candidates for autologous cell therapy in tissue repair and regeneration because of their high angiogenic potential. However, increased progenitor cell apoptosis in diabetes directly limits their success in the clinic. MicroRNAs are endogenous noncoding RNAs that regulate gene expression at the posttranscriptional level, but their roles in BMPC-mediated angiogenesis are incompletely understood. In the present study, we tested the hypothesis that the proangiogenic miR-27b inhibits BMPC apoptosis in Type 2 diabetes. Bone marrow-derived EPCs from adult male Type 2 diabetic db/db mice and their normal littermates db/+ mice were used. MiR-27b expression (real-time PCR) in EPCs was decreased after 24 h of exposure to methylglyoxal (MGO) or oxidized low-density lipoprotein but not high glucose, advanced glycation end products, the reactive oxygen species generator LY83583, or H2O2. The increase in BMPC apoptosis in the diabetic mice was rescued following transfection with a miR-27b mimic, and the increased apoptosis induced by MGO was also rescued by the miR-27b mimic. p53 protein expression and the Bax/Bcl-2 ratio in EPCs (Western blot analyses) were significantly higher in db/db mice, both of which were suppressed by miR-27b. Furthermore, mitochondrial respiration, as measured by oxygen consumption rate, was enhanced by miR-27b in diabetic BMPCs, with concomitant decrease of mitochondrial Bax/Bcl-2 ratio. The 3′ UTR binding assays revealed that both Bax, and its activator RUNX1, were direct targets of miR-27b, suggesting that miR-27b inhibits Bax expression in both direct and indirect manners. miR-27b prevents EPC apoptosis in Type 2 diabetic mice, at least in part, by suppressing p53 and the Bax/Bcl-2 ratio. These findings may provide a mechanistic basis for rescuing BMPC dysfunction in diabetes for successful autologous cell therapy.

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Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes

Journal of Endocrinology ◽

10.1530/joe-12-0356 ◽

2012 ◽

Vol 216 (1) ◽

pp. 1-11 ◽

Cited By ~ 46

Author(s):

Lucy M Hinder ◽

Anuradha Vivekanandan-Giri ◽

Lisa L McLean ◽

Subramaniam Pennathur ◽

Eva L Feldman

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Sciatic Nerve ◽

Peripheral Nerves ◽

Sural Nerve ◽

Tca Cycle ◽

Tricarboxylic Acid ◽

Diabetic Mice ◽

Type 2 Diabetic

Diabetic neuropathy (DN) is the most common complication of diabetes and is characterized by distal-to-proximal loss of peripheral nerve axons. The idea of tissue-specific pathological alterations in energy metabolism in diabetic complications-prone tissues is emerging. Altered nerve metabolism in type 1 diabetes models is observed; however, therapeutic strategies based on these models offer limited efficacy to type 2 diabetic patients with DN. Therefore, understanding how peripheral nerves metabolically adapt to the unique type 2 diabetic environment is critical to develop disease-modifying treatments. In the current study, we utilized targeted liquid chromatography–tandem mass spectrometry (LC/MS/MS) to characterize the glycolytic and tricarboxylic acid (TCA) cycle metabolomes in sural nerve, sciatic nerve, and dorsal root ganglia (DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Leprdb;db/db) and controls (db/+). We report depletion of glycolytic intermediates in diabetic sural nerve and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate (sural nerve only), 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, and lactate), with no significant changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in sural nerve, sciatic nerve, and DRG from diabetic mice. Utilizing LC/electrospray ionization/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids) indb/dbtissue, with a proximal-to-distal increase in oxidative stress, with associated decreased aconitase enzyme activity. We propose a preliminary model, whereby the greater change in metabolomic profile, increase in oxidative stress, and decrease in TCA cycle enzyme activity may cause distal peripheral nerves to rely on truncated TCA cycle metabolism in the type 2 diabetes environment.

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The Efficacy of Red Ginseng in Type 1 and Type 2 Diabetes in Animals

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/593181 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 19

Author(s):

Bin Na Hong ◽

Min Gun Ji ◽

Tong Ho Kang

Keyword(s):

Type 2 Diabetes ◽

Signal Intensity ◽

Diabetic Mice ◽

Red Ginseng ◽

Korean Red Ginseng ◽

Diabetes In Animals ◽

Brainstem Response ◽

Type 2 Diabetic

Diabetes mellitus (DM) is one of the most modern chronic metabolic diseases in the world. Moreover, DM is one of the major causes of modern neurological diseases. In the present study, the therapeutic actions of Korean red ginseng were evaluated in type 1 and type 2 diabetic mouse models using auditory electrophysiological measurement. The comprehensive results from auditory brainstem response (ABR), auditory middle latency response (AMLR), and transient evoked otoacoustic emission (TEOAE) demonstrate auditory functional damage caused by type 1 or 2 DM. Korean red ginseng improved the hearing threshold shift, delayed latencies and signal intensity decrease in type 2 diabetic mice. Type 1 diabetic mice showed a partial improvement in decreasing amplitude and signal intensity, not significantly. We suggest that the Korean red ginseng has a more potent efficacy in hearing loss in insulin resistance type 2 diabetes than in type 1 diabetes.

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Impact of P2Y12 Inhibitory Effects Induced by Clopidogrel on Platelet Procoagulant Activity in Type 2 Diabetes Mellitus Patients

Thrombosis Research ◽

10.1016/j.thromres.2008.10.001 ◽

2009 ◽

Vol 124 (3) ◽

pp. 318-322 ◽

Cited By ~ 28

Author(s):

Dominick J. Angiolillo ◽

Piera Capranzano ◽

Bhaloo Desai ◽

Steven B. Shoemaker ◽

Ronald Charlton ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Procoagulant Activity ◽

Inhibitory Effects

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Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00026.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. E45-E54 ◽

Cited By ~ 13

Author(s):

Minglong Shao ◽

Lechu Yu ◽

Fangfang Zhang ◽

Xuemian Lu ◽

Xiaokun Li ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Combination Treatment ◽

Combined Treatment ◽

Protective Effects ◽

Diabetic Mice ◽

Renal Protection ◽

Glucose Levels

The onset of diabetic nephropathy (DN) is associated with both systemic and renal changes. Fibroblast growth factor (FGF)-21 prevents diabetic complications mainly by improving systemic metabolism. In addition, low-dose radiation (LDR) protects mice from DN directly by preventing renal oxidative stress and inflammation. In the present study, we tried to define whether the combination of FGF21 and LDR could further prevent DN by blocking its systemic and renal pathogeneses. To this end, type 2 diabetes was induced by feeding a high-fat diet for 12 wk followed by a single dose injection of streptozotocin. Diabetic mice were exposed to 50 mGy LDR every other day for 4 wk with and without 1.5 mg/kg FGF21 daily for 8 wk. The changes in systemic parameters, including blood glucose levels, lipid profiles, and insulin resistance, as well as renal pathology, were examined. Diabetic mice exhibited renal dysfunction and pathological abnormalities, all of which were prevented significantly by LDR and/or FGF21; the best effects were observed in the group that received the combination treatment. Our studies revealed that the additive renal protection conferred by the combined treatment against diabetes-induced renal fibrosis, inflammation, and oxidative damage was associated with the systemic improvement of hyperglycemia, hyperlipidemia, and insulin resistance. These results suggest that the combination treatment with LDR and FGF21 prevented DN more efficiently than did either treatment alone. The mechanism behind these protective effects could be attributed to the suppression of both systemic and renal pathways.

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Inhibitory Effect of Metformin on Oxidation of NADH-Dependent Substrates in Rat Liver Homogenate

Physiological Research ◽

10.33549/physiolres.932193 ◽

2011 ◽

pp. 835-839 ◽

Cited By ~ 8

Author(s):

E. PÁLENÍČKOVÁ ◽

M. CAHOVÁ ◽

Z. DRAHOTA ◽

L. KAZDOVÁ ◽

M. KALOUS

Keyword(s):

Type 2 Diabetes ◽

Mitochondrial Respiration ◽

Complex I ◽

Liver Homogenate ◽

Inhibitory Effect ◽

Small Samples ◽

Inhibitory Effects ◽

Experimental Conditions ◽

Wet Weight

Metformin is widely used in the treatment of Type 2 diabetes, however, mechanisms of its antihyperglycemic effect were not yet fully elucidated. Complex I of mitochondrial respiration chain is considered as one of the possible targets of metformin action. In this paper, we present data indicating that the inhibitory effect of metformin can be tested also in liver homogenate. Contrary to previous findings on hepatocytes or mitochondria under our experimental conditions, lower metformin concentrations and shorter time of preincubation give significant inhibitory effects. These conditions enable to study the mechanism of the inhibitory effect of metformin in small samples of biological material (50-100 mg wet weight) and compare more experimental groups of animals because isolation of mitochonria is unnecessary.

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