Summary of Study ST002382

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001532. The data can be accessed directly via it's Project DOI: 10.21228/M8P11T This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

Study ID	ST002382
Study Title	Deep multi-omic profiling reveals extensive mitochondrial remodeling driven by glycemia in early diabetic kidney disease
Study Summary	Changes in mitochondrial energy metabolism are thought to be central to the development of diabetic kidney disease (DKD); however, whether this response is explicitly driven by systemic glucose concentrations remains unknown. Here, we show that titrating blood glucose concentrations in vivo directly impacts mitochondrial morphology and bioenergetics and remodels the mitochondrial proteome in the kidney in early DKD. Mitoproteomic analysis revealed profound metabolic disturbances induced by severe hyperglycemia, including upregulation of enzymes involved in the TCA cycle and fatty acid metabolism, enhanced ketogenesis as well as extensive dysregulation of the mitochondrial SLC25 carrier family. The metabolite and lipid landscape were perturbed by severe hyperglycemia; untargeted metabolomics and lipidomics confirmed the enrichment of TCA cycle metabolites, an increase in triglyceride concentrations, and extensive and specific cardiolipin remodeling. Lowering blood glucose to moderate hyperglycemia stabilized all three omic landscapes, partially prevented changes in mitochondrial morphology and bioenergetics, and improved kidney injury. This study provides insights into altered substrate utilization and energy generation in the kidney early in diabetes, during moderate and severe hyperglycemia and has implications for therapeutic strategies aiming at the reinvigoration of mitochondrial function and signaling in diabetes.
Institute	University of Melbourne
Last Name	Caruana
First Name	Nikeisha
Address	30 Flemington Rd, Parkville VIC 3052
Email	nikeisha.caruana@unimelb.edu.au
Phone	0383442219
Submit Date	2022-11-09
Raw Data Available	Yes
Raw Data File Type(s)	mzXML
Analysis Type Detail	LC-MS
Release Date	2022-12-27
Release Version	1

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Treatment:

Treatment ID:	TR002483
Treatment Summary:	Male Sprague Dawley rats were housed in groups of three rats per cage in a temperature-controlled environment, with a 12 h light/dark cycle and ad libitum access to food and water. Experimental diabetes was induced in six week old male Sprague Dawley rats (200-250 g, n = 35) by i.v. injection of streptozotocin (55 mg/kg, sodium citrate buffer pH 4.5) following an overnight fast, as previously described (80). One group of rats received citrate buffer vehicle (0.42% in sterile saline, pH 4.5) as a non-diabetic control with normal blood glucose (NG) (n = 16). One week following STZ treatment, diabetic rats were further assigned to two groups: standard insulin therapy (n = 17 rats), resulting in severe hyperglycemia (SHG) and intensive insulin therapy (n = 19 rats), resulting in moderate hyperglycemia (MHG) using a single daily insulin injection (long-lasting Humulin NPH; Eli Lilly, Indianapolis, USA) to titrate blood glucose levels to >28 mM (1-2 units, s.c. per day) and ∼20 mM (6-7 units, s.c. per day) as required, respectively. Blood glucose and body weight were monitored weekly. Blood glucose was measured using a handheld glucometer (Accutrend; Boehringer Manheim Biochemica, Manheim, Germany) during the study time course. After the completion of the study, plasma glucose was measured using a colorimetric glucose assay kit from Cayman Chemical Company (Ann Arbor, MI, USA), performed according to the manufacturer’s instructions. Hemoglobin A1c (HbA1c) was determined by a Cobas Integra 400 autoanalyzer (Roche Diagnostics Corporation, USA). Plasma C-peptide was determined using a commercially available ELISA kit (Alpco, Salem, NH, USA) according to the manufacturer’s instructions. In the final week of the study, rats were placed individually into metabolic cages (Iffa Credo, L’Arbresele, France) for 24 hours to collect urine.

Treatment ID:

TR002483

Treatment Summary:

Male Sprague Dawley rats were housed in groups of three rats per cage in a temperature-controlled environment, with a 12 h light/dark cycle and ad libitum access to food and water. Experimental diabetes was induced in six week old male Sprague Dawley rats (200-250 g, n = 35) by i.v. injection of streptozotocin (55 mg/kg, sodium citrate buffer pH 4.5) following an overnight fast, as previously described (80). One group of rats received citrate buffer vehicle (0.42% in sterile saline, pH 4.5) as a non-diabetic control with normal blood glucose (NG) (n = 16). One week following STZ treatment, diabetic rats were further assigned to two groups: standard insulin therapy (n = 17 rats), resulting in severe hyperglycemia (SHG) and intensive insulin therapy (n = 19 rats), resulting in moderate hyperglycemia (MHG) using a single daily insulin injection (long-lasting Humulin NPH; Eli Lilly, Indianapolis, USA) to titrate blood glucose levels to >28 mM (1-2 units, s.c. per day) and ∼20 mM (6-7 units, s.c. per day) as required, respectively. Blood glucose and body weight were monitored weekly. Blood glucose was measured using a handheld glucometer (Accutrend; Boehringer Manheim Biochemica, Manheim, Germany) during the study time course. After the completion of the study, plasma glucose was measured using a colorimetric glucose assay kit from Cayman Chemical Company (Ann Arbor, MI, USA), performed according to the manufacturer’s instructions. Hemoglobin A1c (HbA1c) was determined by a Cobas Integra 400 autoanalyzer (Roche Diagnostics Corporation, USA). Plasma C-peptide was determined using a commercially available ELISA kit (Alpco, Salem, NH, USA) according to the manufacturer’s instructions. In the final week of the study, rats were placed individually into metabolic cages (Iffa Credo, L’Arbresele, France) for 24 hours to collect urine.