Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type-2 diabetes

ABSTRACTType-2 diabetes (T2D) mellitus is a complex metabolic disease commonly caused by insulin resistance in several tissues. We performed a matched two-dimensional metabolic screening in tissue samples from a cohort of 43 multi-organ donors. The intra-individual analysis was assessed across five key-metabolic tissues (serum, adipose tissue, liver, pancreatic islets and muscle), and the inter-individual across three different groups reflecting T2D progression. We identified 92 metabolites differing significantly between non-diabetes and T2D subjects. Carnitines were significantly higher in liver, while lysophosphatidylcholines significantly lower in muscle and serum. An investigation of the progression to overt T2D showed that deoxycholic acid glycine conjugate was significantly higher in liver of pre-diabetes samples while additional increase in T2D was insignificant. A subset of lysophosphatidylcholines were significantly lower in the muscle of pre-diabetes subjects. Overall, the analysis of this unique dataset can increase the understanding of the metabolic interplay between organs in the development of T2D.

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Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes

Scientific Reports ◽

10.1038/s41598-019-45906-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Klev Diamanti ◽

Marco Cavalli ◽

Gang Pan ◽

Maria J. Pereira ◽

Chanchal Kumar ◽

...

Keyword(s):

Type 2 Diabetes ◽

Metabolic Profiling ◽

Molecular Defects

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Abstract 368: The GLP-1 Receptor Agonist Liraglutide Improves Autophagy Impairment in the Diabetic Heart

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.368 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Antoinette Bugyei-Twum ◽

Jennifer Switzer ◽

Krishna K Singh ◽

Kim A Connelly

Keyword(s):

Type 2 Diabetes ◽

Experimental Diabetes ◽

Beclin 1 ◽

Negative Regulator ◽

Diabetic Heart ◽

Tissue Samples ◽

Expression Levels ◽

Cardioprotective Effects ◽

The Impact

Background: Diabetes mellitus is a well-recognized risk factor for the development of heart failure. Although studies with the glucagon-like pepide-1 analog liraglutide—an approved treatment for type 2 diabetes—have demonstrated substantial cardioprotective effects of the drug in both human and experimental diabetes, the underlying mode of action/mechanism of liraglutide remains unclear. Here, we investigate the impact of liraglutide on autophagy—an evolutionary conserved mechanism thought to play an essential role in cell survival during stress—using a rodent model of type 2 diabetes, the Goto Kakizaki (GK) rat. Methods: Thirty-two weeks old male GK rats and sex/age-matched Wistar controls were treated with liraglutide (0.2 mg/kg/day) or PBS twice daily for 8 consecutive weeks. At 40-weeks of age, cardiac structure/function were assessed by echocardiography and LV tissue samples were collected to assess the expression of inducers/markers of autophagy (mTOR, phospho-mTOR, LC3-I/II, p62, and Beclin-1). Results: Autophagy was inhibited in the heart of diabetic GK animals when compared to Wistar controls, as confirmed by a significant increase in mTOR expression/activation—a negative regulator of autophagy. This was further confirmed by an observed decrease in the LC3 II/I ratio in diabetic GK animals when compared to controls (p<0.05). P62 expression levels, however, were found to be significantly upregulated in GK animals with respect to controls (p<0.01); suggesting an impairment or defect in basal autophagy in diabetic GK animals. Liraglutide-treatment—which was associated with an improvement in both HbA1C level and LV hypertrophy in GK animals—resulted a significant reduction in mTOR expression/activation in GK animals when compared to their untreated counterparts. This improvement in autophagy status was further corroborated by an observed increase in LC3 II/I ratio and Beclin-1, as well as a reduction in p62 expression levels. Conclusion: Overall, our data suggests that the cardioprotective effects of liraglutide may stem from its ability to activate autophagy in the diabetic heart and improve autophagy impairment in the setting of type 2 diabetes.

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Increased AQP7 abundance in skeletal muscle from obese men with type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00468.2017 ◽

2018 ◽

Vol 315 (3) ◽

pp. E367-E373 ◽

Cited By ~ 4

Author(s):

Janne Lebeck ◽

Esben Søndergaard ◽

Søren Nielsen

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Protein Abundance ◽

Tissue Samples ◽

Triglyceride Accumulation ◽

Meal Intake ◽

Fasting And Refeeding ◽

Subcutaneous Adipose

Aquaglyceroporin 7 (AQP7) facilitates the transport of glycerol across cell membranes. In mice, fasting and refeeding regulate adipose tissue AQP7 abundance, and a role in controlling triglyceride accumulation in adipose tissue has been proposed. AQP7 is also expressed in skeletal muscle, where its function remains to be determined. Here, the abundance of AQP7 in abdominal subcutaneous adipose tissue (SAT) and skeletal muscle was evaluated in the overnight fasted and postprandial state in eight lean and eight obese men with type 2 diabetes (T2D). A biopsy from SAT and muscle was collected after an overnight fast and 2 h after ingestion of a low-fat test meal. Palmitate turnover was evaluated using a [9,10-3H] palmitate dilution technique. Tissue samples were analyzed by immunoblotting. Meal intake did not affect AQP7 expression in SAT or skeletal muscle. No association between the SAT AQP7 abundance and palmitate turnover was found. SAT AQP7 abundance was similar in lean and obese T2D men, whereas muscle AQP7 abundance was more than fourfold higher in obese T2D men. In conclusion, meal intake did not affect AQP7 protein abundance in SAT or skeletal muscle. In addition, SAT AQP7 expression does not appear to be involved in the regulation of adipose tissue lipolysis. However, in contrast to SAT AQP7, skeletal muscle AQP7 protein abundance is markedly increased in obese T2D men, potentially contributing to the excess lipid accumulation in skeletal muscle in type 2 diabetes.

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Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes

Diabetologia ◽

10.1007/s00125-017-4500-3 ◽

2017 ◽

Vol 61 (3) ◽

pp. 641-657 ◽

Cited By ~ 53

Author(s):

Michele Solimena ◽

Anke M. Schulte ◽

Lorella Marselli ◽

Florian Ehehalt ◽

Daniela Richter ◽

...

Keyword(s):

Type 2 Diabetes ◽

Systems Biology ◽

Organ Donors ◽

Transcriptomic Signature

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Evidence for a Role of Frataxin in Pancreatic Islets Isolated from Multi-Organ Donors with and Without Type 2 Diabetes Mellitus

Hormone and Metabolic Research ◽

10.1055/s-0032-1301920 ◽

2012 ◽

Vol 44 (06) ◽

pp. 471-475 ◽

Cited By ~ 6

Author(s):

S. Del Guerra ◽

V. D'Aleo ◽

G. Gualtierotti ◽

R. Pandolfi ◽

U. Boggi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Pancreatic Islets ◽

Organ Donors

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Plasma Bile Acid Profile in Patients with and without Type 2 Diabetes

Metabolites ◽

10.3390/metabo11070453 ◽

2021 ◽

Vol 11 (7) ◽

pp. 453

Author(s):

Alessandro Mantovani ◽

Andrea Dalbeni ◽

Denise Peserico ◽

Filippo Cattazzo ◽

Michele Bevilacqua ◽

...

Keyword(s):

Type 2 Diabetes ◽

Bile Acid ◽

Deoxycholic Acid ◽

Plasma Concentrations ◽

Ultra Performance Liquid Chromatography ◽

Lower Plasma ◽

Hyodeoxycholic Acid ◽

Liquid Chromatography Tandem Mass ◽

Glycodeoxycholic Acid

A paucity of information currently exists on plasma bile acid (BA) profiles in patients with and without type 2 diabetes mellitus (T2DM). We assayed 14 plasma BA species in 224 patients with T2DM and in 102 nondiabetic individuals with metabolic syndrome. Plasma BA levels were measured with ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) technique. Multivariable linear regression analyses were undertaken to assess associations between measured plasma BA species and T2DM status after adjustment for confounding factors. The presence of T2DM was significantly associated with higher plasma concentrations of both primary BAs (adjusted-standardized β coefficient: 0.279, p = 0.005) and secondary BAs (standardized β coefficient: 0.508, p < 0.001) after adjustment for age, sex, adiposity measures, serum alanine aminotransferase and use of statins or metformin. More specifically, the presence of T2DM was significantly associated with higher levels of plasma taurochenodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid, hyodeoxycholic acid, glycodeoxycholic acid, glycolithocholic acid, deoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid and glycodeoxycholic acid (adjusted-standardized β coefficients ranging from 0.315 to 0.600; p < 0.01 or less), as well as with lower plasma levels of cholic acid (adjusted-standardized β coefficient: −0.250, p = 0.013) and taurocholic acid (adjusted-standardized β coefficient: −0.309, p = 0.001). This study shows that there are marked differences in plasma BA profiles between patients with and without T2DM. Further research will be needed to better understand how these differences in plasma BA profiles may interplay with the pathophysiology of T2DM.

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Protective Effect of Ginkgo biloba and Magnetized Water on Nephropathy in Induced Type 2 Diabetes in Rat

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/1785614 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Ahmed E. Zayed ◽

Ahmed Saleh ◽

Asmaa M. S. Gomaa ◽

Mahmoud Abd-Elkareem ◽

Mamdouh M. Anwar ◽

...

Keyword(s):

Type 2 Diabetes ◽

Protective Effect ◽

Ginkgo Biloba ◽

Kidney Tissue ◽

Diabetic Rat ◽

Control Group ◽

Blood Levels ◽

Tissue Samples ◽

Magnetized Water

We aimed in our current study to explore the protective effect of Ginkgo biloba (GB) and magnetized water (MW) against nephrotoxicity associating induced type 2 diabetes mellitus in rat. Here, we induced diabetes by feeding our lab rats on a high fat-containing diet (4 weeks) and after that injecting them with streptozotocin (STZ). We randomly divided forty rats into four different groups: nontreated control (Ctrl), nontreated diabetic (Diabetic), Diabetic+GB (4-week treatment), and Diabetic+MW (4-week treatment). After the experiment was finished, serum and kidney tissue samples were gathered. Blood levels of glucose, triglycerides, cholesterol, creatinine, and urea were markedly elevated in the diabetic group than in the control group. In all animals treated with GB and MW, the levels of urea, creatinine, and glucose were significantly reduced (all P<0.01). GB and MW attenuated glomerular and tubular injury as well as the histological score. Furthermore, they normalized the contents of glutathione reductase and SOD2. In summary, our data showed that GB and MW treatment protected type 2 diabetic rat kidneys from nephrotoxic damages by reducing the hyperlipidemia, uremia, oxidative stress, and renal dysfunction.

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