TY - JOUR
T1 - Elevations in the fasting serum Proinsulin-to-C-peptide ratio precede the onset of type 1 diabetes
AU - Sims, Emily K.
AU - Chaudhry, Zunaira
AU - Watkins, Renecia
AU - Syed, Farooq
AU - Blum, Janice
AU - Ouyang, Fangqian
AU - Perkins, Susan M.
AU - Mirmira, Raghavendra G.
AU - Sosenko, Jay
AU - DiMeglio, Linda A.
AU - Evans-Molina, Carmella
N1 - Funding Information:
Samples from at-risk subjects were obtained through a TrialNet ancillary study to the TN-01 Pathway to Prevention study funded by National Institutes of Health (NIH) grants U01-DK-061010, U01-DK-061034, U01-DK- 061042, U01-DK-061058, U01-DK-085465, U01-DK-085453, U01-DK-085461, U01-DK- 085463, U01-DK-085466, U01-DK-085499, U01-DK-085504, U01-DK-085505, U01-DK- 085509, U01-DK-103180, U01-DK-103153, U01-DK-085476, and U01-DK-103266 and JDRF. The manuscript was also supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants K08-DK-103983 (to E.K.S.), UC4-DK-104166 (to R.G.M. and C.E.-M.), R01-DK-093954 (to C.E.-M.), and P30- DK-097512; a Pediatric Endocrine Society Clinical Scholar Award (to E.K.S.); U.S. Department of Veterans Affairs Merit Award I01BX001733 (to C.E.-M.); JDRF Pioneer Award and Strategic Research Agreement (to J.B., L.A.D., and C.E.-M.); JDRF grants 47-2012-744 (to L.A.D.), 2-SRA-2014- 299-Q-R, SRA-2014-41, and 47-2012-744; and NIH National Center for Advancing Translational Sciences Clinical and Translational Sciences Award UL1TR000006 UO1 (to R.W.).
Publisher Copyright:
© 2016 by the American Diabetes Association.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - OBJECTIVE We tested whether an elevation in the serum proinsulin-to-C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum(ER) dysfunction,was associated with progression to type 1 diabetes. RESEARCH DESIGN AND METHODS Fasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibodypositive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMImatched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. RESULTS Although absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). CONCLUSIONS These data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase.
AB - OBJECTIVE We tested whether an elevation in the serum proinsulin-to-C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum(ER) dysfunction,was associated with progression to type 1 diabetes. RESEARCH DESIGN AND METHODS Fasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibodypositive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMImatched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. RESULTS Although absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). CONCLUSIONS These data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase.
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U2 - 10.2337/dc15-2849
DO - 10.2337/dc15-2849
M3 - Article
C2 - 27385327
AN - SCOPUS:84986230525
VL - 39
SP - 1519
EP - 1526
JO - Diabetes Care
JF - Diabetes Care
SN - 1935-5548
IS - 9
ER -