Article pubs.acs.org/jpr
Serum Metabolic Signatures of Fulminant Type 1 Diabetes Jingyi Lu,†,§ Jian Zhou,†,§ Yuqian Bao,† Tianlu Chen,‡ Yinan Zhang,‡ Aihua Zhao,‡ Yunping Qiu,⊥ Guoxiang Xie,⊥ Congrong Wang,† Wei Jia,*,⊥ and Weiping Jia*,† †
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai 200233, PR China ‡ X-omics Research Centre for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, PR China ⊥ Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina 28081, United States S Supporting Information *
ABSTRACT: Fulminant type 1 diabetes (FT1DM) is a relatively new clinical entity featured by acute destruction of pancreatic beta cells. Clinical consequences of FT1DM could be fatal when timely medications are not provided, suggesting the particular importance of rapid and accurate diagnosis. Here we report a serum metabonomics study of FT1DM patients, together with healthy control subjects (NC), type 2 diabetes (T2DM), classic type 1 diabetes (T1DM), and diabetic ketoacidosis (DKA) patients, with the aim of discovering metabolic markers associated with FT1DM. A total of 79 subjects were enrolled (22 NC, 22 T1DM, 22 T2DM, 8 DKA and 5 FT1DM) and the serum metabolic profiling of fasting blood samples was performed using gas chromatography time-of-flight mass spectrometry (GC-TOFMS) coupled with multivariate and univariate statistical analyses. Serum metabolites differentially expressed in FT1DM relative to NC, or to T2DM, T1DM and DKA were identified. Three metabolite markers, 5-oxoproline, glutamate, and homocysteine, were significantly altered among FT1DM, T2DM, T1DM, and DKA. In addition, the three metabolite markers, 5-oxoproline, glutamate, and homocysteine, presented similar patterns of distribution across groups. The results showed that the metabolic signatures of FT1DM identified in this study could be of potential clinical significance for the accurate diagnosis of FT1DM. KEYWORDS: fulminant type 1 diabetes, FT1DM, serum, metabonomics, metabolomics, biomarker
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INTRODUCTION Fulminant type 1 diabetes (FT1DM) is a subtype of T1DM first reported in 2000.1 This disease stems from a rapid and almost complete destruction of pancreatic beta cells as well as alpha cells,2 and is characterized by abrupt onset of diabetic symptoms (e.g., polyuria and thirst), rapid progression to ketosis or ketoacidosis (usually less than 1 week), remarkably reduced pancreatic beta cell secretory capacity and elevated serum pancreatic enzyme levels. To date, FT1DM is mainly reported in East Asia, predominantly in Japan. FT1DM is estimated to account for 15−20% T1DM patients that feature the onset of ketosis or ketoacidosis3 in Japanese population and the prevalence was estimated to be 8.9% in all T1DM patients and 0.2% in newly diagnosed all diabetic patients.4 In Caucasians, however, only three cases have been reported.5 Despite the low prevalence, the consequences of FT1DM could be fatal. Without timely and appropriate management, the death of the patient is almost inevitable, highlighting the critical importance of early diagnosis of the disease. On the other hand, flu-like symptoms (such as fever, headache and cough) and abdominal symptoms (such as vomiting and diarrhea) were observed in most (71.7% and 72.5%, respectively) FT1DM patients, which sometimes make it more difficult to diagnose © 2012 American Chemical Society
the disease. In addition, common forms of diabetes such as classic type 1 diabetes (T1DM) share many clinical manifestations with FT1DM, especially when ketoacidosis is a concomitant, confounding the accurate diagnosis of FT1DM. Metabonomics is a rapidly evolving technology by which an entire spectrum of endogenous metabolites in cells, biofluids or tissues following genetic or environmental interventions is measured quantitatively.6 There is mounting evidence that metabonomics can provide important insight into biomarker discoveries, toxicity evaluation and the pathogenic nature of various diseases. 7−11 In this context, we conducted a comprehensive metabonomic analysis of serum samples in FT1DM patients along with healthy controls, T1DM, T2DM and diabetic ketoacidosis (DKA) subjects using a gas chromatography-time-of-flight mass spectrometry (GCTOFMS). The purpose of our study was to identify metabolic signatures as well as potential metabolite-based diagnostic markers of FT1DM. Received: June 12, 2012 Published: August 16, 2012 4705
dx.doi.org/10.1021/pr300523x | J. Proteome Res. 2012, 11, 4705−4711
Journal of Proteome Research
Article
Table 1. The Characteristics of the Study Samplesa parameters
NC
T2DM
T1DM
DKA
FT1DM
N (male/female) Age (yrs) BMI (kg/m2) SBP (mmHg) DBP (mmHg) ALT (u/L) AST (u/L) HDL-C (mmol/L) LDL-C (mmol/L) Bun (mmol/L) SCr (μmol/L) UA (μmol/L) FPG (mmol/L) 2hPG (mmol/L) PG at onset (mmol/L) HbA1c (%) CP(0 min) (ng/mL) CP(30 min) (ng/mL) CP(120 min)(ng/mL)
22/0 38.68 ± 10.37 23.38 ± 3.17a 113.64 ± 9.02a 76.59 ± 5.21 26.77 ± 16.89a 25.32 ± 10.2a 1.32 ± 0.24 2.68 ± 0.71 5.43 ± 1.15a 77.73 ± 10.04a 334.41 ± 53.87a 4.87 ± 0.46ab 4.59 ± 1.40ab / 5.4 ± 0.31abc 1.22 ± 0.55a 3.86 ± 1.46abc 3.54 ± 1.47abc
22/0 43.5 ± 10.75 27.2 ± 4.31abcd 129.86 ± 16.54a 84.77 ± 15.04 34.68 ± 18.63b 26.73 ± 10.89b 1.01 ± 0.19a 3.02 ± 0.91 5.11 ± 0.86b 72.86 ± 13.76b 339.05 ± 55.88b 8.91 ± 3.23a 16.35 ± 4.65a / 8.44 ± 1.63a 1.85 ± 0.89bcd 3.03 ± 1.68def 4.59 ± 2.72def
22/0 43.41 ± 15.86 21.89 ± 3.25b 125.86 ± 18.95 81.77 ± 12.89 23.27 ± 19.24c 20.45 ± 11.79c 1.45 ± 0.54a 3.25 ± 1.10a 5.60 ± 2.17c 79.82 ± 35.75c 299.77 ± 62.12c 9.48 ± 5.01b 16.79 ± 7.08b / 10.25 ± 3.01bd 0.67 ± 0.81b 1.00 ± 1.47ad 1.27 ± 1.64ad
4/4 45.00 ± 15.54 22.56 ± 4.67c 126.25 ± 13.02 76.75 ± 13.36 16.88 ± 5.84d 15.63 ± 4.72d 1.19 ± 0.25 2.63 ± 1.17 4.26 ± 2.49d 57.13 ± 15.99d 415.38 ± 234.79 / / 20.76 ± 3.93a 10.60 ± 2.41ce 0.68 ± 0.55c 0.82 ± 0.91be 1.13 ± 1.38be
5/0 38.40 ± 12.88 21.40 ± 1.59d 119.2 ± 12.19 72.00 ± 9.97 173.6 ± 188.93abcd 263.4 ± 331.17abcd 1.03 ± 0.42 1.90 ± 0.21a 11.82 ± 5.26abcd 208.2 ± 77.44abcd 576.4 ± 290.64abc / / 44.84 ± 13.98a 6.30 ± 0.23de 0.03 ± 0.02ad 0.03 ± 0.02cf 0.06 ± 0.04cf
Values are presented as mean ± standard deviation. Same superscript letter (a, b, c, d, e, and f) between groups indicates significant difference at P < 0.05 after bonferroni correction. FT1DM, fulminant T1DM; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; ALT, aspartate aminotransferase; AST, alanine aminotransferase; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; BUN, blood urea nitrogen; SCr, serum creatinine; UA, uric acid; FPG, fasting plasma glucose; PG, plasma glucose; CP, C peptide; /, not available. a
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MATERIALS AND METHODS
and low-density lipoprotein-cholesterol), HbA1c, blood pressure, weight, body mass index (BMI), C peptide and liver and kidney functions were determined as previously described.13
Subjects
A total of 79 subjects (22 normal healthy subjects, 22 classic T1DM without acute complications, 22 newly diagnosed T2DM without any antidiabetic medications, 8 DKA and 5 FT1DM) were recruited in the current study. Only males were selected except for the DKA group (4 males and 4 females). The diagnostic criteria for the 5 FT1DM patients were based on published literature3 and included all of the following: (1) occurrence of diabetic ketosis or ketoacidosis soon (around 7 days) after the onset of hyperglycemic symptoms (elevation of urinary and/or serum ketone bodies at first visit); (2) plasma glucose ≥16.0 mmol/L and glycated hemoglobin level (HbA1c) < 8.5% at first visit; and (3) fasting serum C-peptide level
