451 Islet loss and engraftment markers after TPIAT
Tuesday November 17, 2015 from 11:00 to 12:30
Plenary Room 1

Melena D Bellin, United States

Assistant Professor

Pediatric Endocrinology

University of Minnesota


Islet loss and engraftment markers after TPIAT

Melena Bellin1,2, Sahar Usmani -Brown3, Ty B Dunn1, K. Louise Berry1, Srinath Chinnakotla1,2, Timothy L Preutt1, Joshua J Wilhelm1, Thomas Gilmore1, Antoinette Moran2, Kevan Herold4, Bernhard J Hering1, Gregory Beilman1.

1Surgery, University of Minnesota, Minneapolis, MN, United States; 2Pediatrics, University of Minnesota, Minneapolis, MN, United States; 3L2 Diagnostics, New Haven, CT, United States; 4Internal Medicine, Yale School of Medicine, New Haven, CT, United States

Substantial islet loss is proposed to occur in total pancreatectomy with islet autotransplantation (TPIAT), induced by islet isolation and the post-infusion instant blood mediated inflammatory reaction (IBMIR).  Early measures of islet loss and islet engraftment are needed for clinical monitoring and to allow rapid study of novel therapies to enhance islet engraftment. 
In this single center clinical cohort study, patients (age >11 years) with chronic pancreatiits undergoing TPIAT have frequent serum samples obtained in the first month post-TPIAT, for measures including unmethylated insulin (INS) DNA (expressed as ratio of unmethylated:methylated INS DNA), as a marker specific to beta cell destruction.  Patients return at 3 months to assess islet engraftment by IV glucose tolerance tests (IVGTT), glucose-potentiated arginine stimulation (GPAIS), and mixed meal tolerance tests (MMTT).  The acute C-peptide response to glucose (ACRglu) and the glucose-potentiated acute C-peptide response to arginine (ACRpot) are calculated from the IVGTT and GPAIS respectively, and AUC C-peptide and AUC glucose from MMTT.
To date, 16 TPIAT recipients have been studied with islet functional testing at 3 months post-TPIAT, with serum unmethylated INS DNA results also available for the first 8 recipients.  Patients had a mean age of 31 ±15 years; 8/16 were male.  Mean islet mass transplanted was 315,722 ±174,320 islet equivalents (IEQ), with all islets transplanted intraportally in 11/16.  Unmethylated INS DNA was elevated post-IAT compared to pre-IAT, with a median peak 4-fold higher than baseline (p=01, figure 1).  The highest levels of unmethylated INS DNA were observed within the first 24 hours post-IAT in 7/8 recipients and correlated with islet mass infused (r=0.82, p=0.01); in some recipients, later variable elevations were observed, possibly reflecting delayed apoptosis and inflammation.   In simple linear regression, the ACRglu and ACRpot correlated with total and hepatic islet mass transplanted (table 1).  However, ACRglu and ACRpot did not correlate with peak or area under the curve for unmethylated insulin DNA, adjusted for islet mass transplanted. 
Unmethylated INS DNA provides a novel marker by which to measure islet loss, and confirms that transplanted islet mass is partially lost, as suspected based on pre-clinical data.  As expected, ACRglu and ACRpot at 3 months post-transplant correlated strongly with the islet mass transplanted, but with notable variability suggestive of differential islet engraftment.  In this small cohort, the unmethylated insulin DNA levels did not predict functional status at 3 months.  However, a larger cohort of patients will be needed to determine if these early measures predict subsequent islet function.

Grant support: NIH / 5R03-DK102469-02; University of Minnesota CTSI K-to-R award..

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