Dataset Information

Quantitative Proteome Analysis Reveals Increased Content of Basement Membrane Proteins in Arteries from Patients with Type 2 Diabetes and Lower Levels among Metformin Users

ABSTRACT: We analyzed non-atherosclerotic repair arteries gathered at coronary by-pass operations from 30 patients with type 2 diabetes, as well as from 30 age- and gender-matched non-diabetic individuals. Quantitative proteome analysis was done by iTRAQ-labelling and LC-MS/MS analysis on individual arterial samples. The amounts of the basement membrane (BM) components, alpha-1- and alpha-2- type IV collagen, gamma-1- and beta-2-laminin were significantly increased in patients with diabetes. Moreover, the expressions of basement membrane components and other vascular proteins were significantly lower among metformin users, as compared to non-users. Patients treated with or without metformin had similar levels of HbA1c, cholesterol and blood pressure. In addition, quantitative histomorphometry showed increased area fractions of collagen-stainable material in tunica intima and media among patients with diabetes.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Artery

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Hans Christian Beck

LAB HEAD: Hans Christian Beck

PROVIDER: PXD002214 | Pride | 2017-02-20

REPOSITORIES: Pride

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Quantitative Proteome Analysis Reveals Increased Content of Basement Membrane Proteins in Arteries From Patients With Type 2 Diabetes Mellitus and Lower Levels Among Metformin Users.

Preil Simone A R SA Kristensen Lars P LP Beck Hans C HC Jensen Pia S PS Nielsen Patricia S PS Steiniche Torben T Bjørling-Poulsen Marina M Larsen Martin R MR Hansen Maria L ML Rasmussen Lars M LM

Circulation. Cardiovascular genetics 20150914 5

<h4>Background</h4>The increased risk of cardiovascular diseases in type 2 diabetes mellitus has been extensively documented, but the origins of the association remain largely unknown. We sought to determine changes in protein expressions in arterial tissue from patients with type 2 diabetes mellitus and moreover hypothesized that metformin intake influences the protein composition.<h4>Methods and results</h4>We analyzed nonatherosclerotic repair arteries gathered at coronary bypass operations f ...[more]

PMID: 26371159

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Project description:Metformin is a type 2 diabetes medication which extends life span across species when given from young adulthood onwards; late life effects of metformin are not well understood. Here we used C. elegans to investigate the outcome of metformin treatment initiated late in life. We found that, contrary to young age administration, old age metformin treatment interferes with energy homeostasis and shortens life span by aggravating age-associated mitochondrial dysfunction. Nematode mutants defective in mitochondrial respiration, mitochondrial biogenesis and mitochondrial quality control were highly susceptible to metformin killing already at young age while insulin receptor deficient nematodes carrying healthier mitochondria were protected from late life metformin toxicity. In the mammalian cell culture model of replicative senescence metformin killing correlated with loss of mitochondrial membrane potential and strong reduction of systemic ATP levels. Reduced ATP levels and depletion of lipid stores consistent with energy deficit were observed also in nematodes following late life metformin treatment. At the molecular level young animals responded to metformin by inducing adaptive stress responses and longevity-assurance pathways while old nematodes demonstrated a protein expression signature consistent with lipid turnover and energy deficit. Ectopic ATP supplementation was sufficient to alleviate metformin toxicity in human skin fibroblasts highlighting the key contribution of energy deficit to the detrimental effect of metformin. Also, co-exposure with rapamycin, known to stabilize cellular ATP levels under conditions of mitochondrial failure, significantly reduced metformin-inflicted lethality in both cells and old animals. In summary we uncovered a novel negative synergism between metformin treatment and mitochondrial dysfunction which gains importance late in life and may limit therapeutic benefits of metformin for older patients; these side effects can partially be overcome by co-treatment with agents stabilizing cellular ATP levels such as rapamycin.

			Action	DRS
	AMix1.msf	Msf
	BMix2.msf	Msf
	CMix3.msf	Msf
	DMix4.msf	Msf
	EMix5.msf	Msf