Abdul Jaleel

Benjamin J. Madden

Bojanovski

Cakatay

Dawn M. Morse

De Feo

Ghiselli

Gregory C. Henderson

K. Sreekumaran Nair

Katherine A. Klaus

McGregor

Nair

Orpiszewski

Srinivas Gopala

Telci

Zannis

English

PubMed


                  OBJECTIVE
                  The accumulation of old and damaged proteins likely contributes to complications of diabetes, but currently no methodology is available to measure the relative age of a specific protein alongside assessment of posttranslational modifications (PTM). To accomplish our goal of studying the impact of insulin deficiency and hyperglycemia in type 1 diabetes upon accumulation of old damaged isoforms of plasma apolipoprotein A-1 (ApoA-1), we sought to develop a novel methodology, which is reported here and can also be applied to other specific proteins.
               
               
                  RESEARCH DESIGN AND METHODS
                  To label newly synthesized proteins, [ring-13C6]phenylalanine was intravenously infused for 8 h in type 1 diabetic participants (n = 7) during both insulin treatment and 8 h of insulin deprivation and in nondiabetic participants (n = 7). ApoA-1 isoforms were purified by two-dimensional gel electrophoresis (2DGE) and assessment of protein identity, PTM, and [ring-13C6]phenylalanine isotopic enrichment (IE) was performed by tandem mass spectrometry.
               
               
                  RESULTS
                  Five isoforms of plasma ApoA-1 were identified by 2DGE including ApoA-1 precursor (pro-ApoA-1) that contained the relatively highest IE, whereas the older forms contained higher degrees of damage (carbonylation, deamidation) and far less IE. In type 1 diabetes, the relative ratio of IE of [ring-13C6]phenylalanine in an older isoform versus pro-ApoA-1 was higher during insulin deprivation, indicating that de novo synthesized pro-ApoA-1 more rapidly accumulated damage, converting to mature ApoA-1.
               
               
                  CONCLUSIONS
                  We developed a mass spectrometry–based methodology to identify the relative age of protein isoforms. The results demonstrated accelerated oxidative damage to plasma ApoA-1, thus offering a potential mechanism underlying the impact of poor glycemic control in type 1 diabetic patients that affects a patient's risk for vascular disease.
               </jats:sec

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Identification of De Novo Synthesized and Relatively Older Proteins: Accelerated Oxidative Damage to De Novo Synthesized Apolipoprotein A-1 in Type 1 Diabetes

Identification of De Novo Synthesized and Relatively Older Proteins: Accelerated Oxidative Damage to De Novo Synthesized Apolipoprotein A-1 in Type 1 Diabetes

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