Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes
Authors: Sims Emily K. , Bahnson Henry T. , Nyalwidhe Julius , Haataja Leena , Davis Asa K. , Speake Cate , DiMeglio Linda A. , Blum Janice , Morris Margaret A. , Mirmira Raghavendra G. , Nadler Jerry , Mastracci Teresa L. , Marcovina Santica , Qian Wei-Jun , Yi Lian , Swensen Adam C. , Yip-Schneider Michele , Schmidt C. Max , Considine Robert V. , Arvan Peter , Greenbaum Carla J. , Evans-Molina Carmella ,   T1D Exchange Residual C-peptide Study Group, Willi Steven , Calvano Tammy , Klingensmith Georgeanna , Haro Heidi , Weinstock Ruth , Bzdick Suzan , Goland Robin , Greenberg Ellen , Lee Joyce , Eason Ashley , DiMeglio Linda , Woerner Stephanie , Ahmann Andrew , Fitch Rebecca , Bethin Kathleen , Ecker Michelle , Hirsch Irl , Peterson Christina , Liljenquist David , Robison Brandon , Bergenstal Richard , Olson Beth , Cengiz Eda , Steffen Amy , Peters Anne , Hinton Perez , McGill Janet , Buechler Lori , Tsalikian Eva , Cabbage Joanne , Clements Mark , Hester Lois , Kruger Davida , Remtema Heather , Schatz Desmond , Thomas Jamie , Zipf William , Seiple Diane , Rodriguez Henry , Henson Danielle , Simmons Jill , Brendle Faith , Nathan Brandon , Schmid Kara , Arnold Kathleen , Sellers Sharon , Harlan David , Hubacz Lisa , Buse John , Tricome Julie , Rickels Michael , Dalton-Bakes Cornelia , Schroeder Leroy , Roark Amanda , Potter Amy , Brendle Faith 
Published: December 2018

OBJECTIVE
Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin.

RESEARCH DESIGN AND METHODS
C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but &lt;0.2 nmol/L; and 3) C-peptide &lt;0.017 nmol/L. Longitudinal samples were analyzed from C-peptide–positive subjects with diabetes after 1, 2, and 4 years.

RESULTS
Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (&gt;3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (&lt;0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (&lt;0.017 nmol/L) residual C-peptide.

CONCLUSIONS
In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide.