Non-alcoholic fatty liver disease (NAFLD) affects more than 70% of patients with type 2 diabetes mellitus (T2DM) and has become one of the most common metabolic liver diseases worldwide. To date, treatments specifically targeting NAFLD do not exist. Oxidative stress and insulin resistance have been implicated in the pathogenesis of NAFLD in diabetes. Accordingly, the goal of this present study was to determine whether Ellagic acid (EA), a natural antioxidant polyphenol found in berries and nuts, mitigates hepatic oxidative stress and insulin resistance in T2DM rats, and thus alleviates NAFLD. Using adult female Goto Kakizaki (GK) rats, a non-obese and spontaneous model of T2DM, we found that EA treatment significantly lowered fasting blood glucose and reduced insulin resistance, as shown by a 21.8% reduction in the homeostasis model assessment index of insulin resistance (HOMA-IR), while triglyceride and total cholesterol levels remained unchanged. Increased hepatic lipid accumulation and oxidative stress present in diabetic GK rats was markedly reduced with EA treatment. This effect was associated with a downregulation of the NADPH oxidase subunit, p47-phox, and overexpression of NF-E2-related factor-2 (NRF2). Moreover, EA was able to decrease the hepatic expression of hypoxia-inducible factor (HIF-α), a transcription factor linked to hypoxia and hepatic steatosis. We further showed that EA treatment activated an insulin signaling pathway in the liver, as evidenced by increased levels of phosphorylated Akt (Ser 473). In conclusion, our results demonstrate that EA diminishes blood glucose levels and potently suppress NAFLD in diabetic rats via mechanisms that involve reductions in p47-phox and HIF-α, upregulation of NRF2 and enhancement of the Akt signaling pathway in the liver. Together, these results reveal that EA improves hepatic insulin sensitivity and lipid metabolism as a result of its antioxidant effects. This implies an anti-diabetic effect of EA with beneficial effects for the treatment of hepatic complications in T2DM.
We report a case of loss of diabetic control in a patient given high doses of inhaled fluticasone propionate for asthma.A 67 year old man who had had asthma for 10 years was referred for respiratory assessment. He had had noninsulin dependent diabetes mellitus for 40 years and was taking glibenclamide 5 mg and metformin 1700 mg daily. Glycaemic control was monitored every six weeks in an outpatient clinic using the percentage of glycated haemoglobin (haemoglobin A 1c ) (Corning-Drew Glycomat low pressure chromatography system).1 The normal range is < 6% and the within batch coefficient of variation is 2.6% and 1.5% for concentrations of 7% and 10% respectively. During the previous year he had had only occasional trace glycosuria ( < 2 positive urinary glucose readings a week) and glycated haemoglobin concentrations (measured every 8 weeks) ranged from 7.0% to 7.3% (data not shown). His asthma treatment comprised ipratropium bromide 0.5 mg and salbutamol 5 mg by nebuliser four times daily. Computed spirometry (12 hours after his last nebuliser) showed that forced expiratory volume in 1 second was 1.48 litres (45% of predicted values) and 1.98 litres 30 minutes after bronchodilatation (Morgan plethysmograph). He had taken no other drugs and no oral corticosteroids in the previous 6 months. He did not drink alcohol or smoke. He was meticulous in taking his treatment and in recording his peak expiratory flow rate twice daily (morning and evening before treatment using a hand held mini-Wright meter) and urinary glucose measurements (Baker Diagnostics).At week 0 he started treatment with inhaled fluticasone propionate 2000 g per day by metered dose inhaler through a Volumatic spacer device (figure). During the next 30 weeks of monitoring he did not take oral corticosteroids, his diabetic treatment and strict diet and exercise regimens remained unchanged, and his weight remained stable. After starting inhaled fluticasone propionate subjective breathlessness and wheeze improved and average weekly peak expiratory flow rate increased from 410 l/min to 440 l/min, but he developed persistent glycosuria during week 3. All 28 urinary glucose measurements were positive for glucose in weeks 3 and 4 and the dose of inhaled fluticasone propionate was thus reduced in a stepwise fashion to 500 g per day in week 14.To our knowledge, deterioration in diabetes has not been documented with the use of inhaled corticosteroids. Furthermore, tolerance to the hyperglycaemic effect of systemic corticosteroids might have explained the subsequent improvement in diabetic control between weeks 15 and 24. 4 With his consent we rechallenged him (single blind fashion) by increasing his daily dose of inhaled fluticasone propionate from 500 g to 1000 g in week 25. Within a week he developed glycosuria (from week 24 to 28, 21 out of 70 urinary readings were positive for glucose). Glycosuria resolved after reducing the dose of fluticasone propionate.In this case the administration of high dose inhaled fluticasone propionate was matched by both a ris...
Background Advanced type 2 diabetes mellitus (T2DM) accelerates vascular smooth muscle cell (VSMC) dysfunction which contributes to the development of vasculopathy, associated with the highest degree of morbidity of T2DM. Lysine acetylation, a post-translational modification (PTM), has been associated with metabolic diseases and its complications. Whether levels of global lysine acetylation are altered in vasculature from advanced T2DM remains undetermined. We hypothesized that VSMC undergoes dysregulation in advanced T2DM which is associated with vascular hyperacetylation. Methods Aged male Goto Kakizaki (GK) rats, a non-obese murine model of T2DM, and age-matched male Wistar rats (control group) were used in this study. Thoracic aortas were isolated and examined for measurement of global levels of lysine acetylation, and vascular reactivity studies were conducted using a wire myograph. Direct arterial blood pressure was assessed by carotid catheterization. Cultured human VSMCs were used to investigate whether lysine acetylation participates in high glucose-induced reactive oxygen species (ROS), a crucial factor triggering diabetic vascular dysfunction. Results The GK rats exhibited marked glucose intolerance as well as insulin resistance. Cardiovascular complications in GK rats were confirmed by elevated arterial blood pressure and reduced VSMC-dependent vasorelaxation. These complications were correlated with high levels of vascular global lysine acetylation. Human VSMC cultures incubated under high glucose conditions displayed elevated ROS levels and increased global lysine acetylation. Inhibition of hyperacetylation by garcinol, a lysine acetyltransferase and p300/CBP association factor (PCAF) inhibitor, reduced high glucose-induced ROS production in VSMC. Conclusion This study provides evidence that vascular hyperacetylation is associated with VSMC dysfunction in advanced T2DM. Understanding lysine acetylation regulation in blood vessels from diabetics may provide insight into the mechanisms of diabetic vascular dysfunction, and opportunities for novel therapeutic approaches to treat diabetic vascular complications.
Vascular complications are the main problems faced by patients with Type 2 Diabetes Mellitus (T2DM). In addition to endothelial dysfunction, vascular smooth muscle cell (VSMC) dysfunction is postulated to play a crucial role in the development of diabetic vascular complications. Recent studies from our laboratory have demonstrated that acetylation of lysine residues, a posttranslational modification, is increased in vascular tissue exposed to metabolic disorders, such as diabetes. We hypothesized that diabetic conditions would dysregulate lysine deacetylases and acetyltransferases in VSMC, consequently leading to increased global lysine acetylation in diabetic blood vessels. Using male adult Goto‐Kakizaki (GK) rats (16‐weeks‐old) as a model of non‐obese type 2 diabetes and their respective Wistar controls, we found that these diabetic rats exhibited high levels of fasting blood glucose (191 ± 12 vs. 98±7 mg/dL vs. controls, p<0.05), as well as hemoglobin A1C (6.82 ± 0.93 vs. 5.2 ±0.2 % controls, p<0.01). Through direct measurement of blood pressure via right carotid catheterization, we also found greater systolic blood pressure in the GK group (166.57 ±24.27 vs. 124.58 ±17.07 controls, p<0.01). This effect was accompanied by high levels of global lysine acetylation in GK blood vessels (3.3 fold of increase vs. control, p<0.001). To test our hypothesis that VSMC is a major cell type in blood vessels contributing to increased vascular lysine acetylation in diabetic conditions, we utilized isolated aortic VSMC from GK rats in primary cultures. After euthanasia with isoflurane (via nasal 5% in 100% O2), thoracic aortas from GK rats were dissected and VSMC were isolated by an enzymatic digestion method. Phenotypically, VSMC from GK rats exhibited an enhanced proliferative phenotype in comparison to VSMC from Wistar control rats (Figure 1). Strikingly, we found that VSMC from GK rats exhibited a marked decrease in SIRT‐1 deacetylase expression (3.5‐fold decrease vs. control, p<0.05). Moreover, expression of the acetyltransferase PCAF was increased in VSMC from GK rats (1.5‐fold increase vs. control, p<0.05). Taken together, our in vitro results suggest that downregulation of SIRT‐1 and upregulation of PCAF may mediate the increased levels of global lysine acetylation in diabetic blood vessels, confirming our hypothesis. To further this investigation, we will identify the proteins that are specifically acetylated in diabetic VSMC through mass spectrometry analysis, as well as the effects on global lysine acetylation when overexpressing SIRT‐1 in VSMC.Support or Funding InformationIn‐House Grant, NYITThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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