CONTEXT:Approximately 20% of patients with chronic pancreatitis achieve insulin independence one year after total pancreatectomy with islet autotransplantation (TPIAT), an outcome associated with younger age and lower pre-transplant HbA1c. The contribution of diabetes-related genetics to TPIAT outcomes is unknown. Genetic risk scores (GRS) are associated with C-peptide levels in type 1 (T1D) and type 2 (T2D) diabetes. OBJECTIVE:To evaluate whether T1D and T2D GRS and partitioned metabolic polygenic scores (PGS) are associated with diabetes before TPIAT and metabolic outcomes one year after transplant. METHODS:We genotyped 318 patients with chronic pancreatitis undergoing TPIAT in the multicenter "Advancing Treatment for Pancreatitis: A Prospective Observational Study of TPIAT" using a global screening array. Regression models assessed associations of T1D- and T2D-GRS and metabolic PGS with diabetes outcomes one year after TPIAT. RESULTS:Participants were 29±17 years old, 61% female, 84% non-Hispanic White, and 13% had diabetes prior to transplant. T2D-GRS was higher among those with pre-TPIAT diabetes (-0.6±0.3 versus -0.8±0.2, p=0.003) and was associated with higher pre-transplant HbA1c (β=0.19 % per 1-SD [95% CI:0.04, 0.33], p = 0.011). Adjusted for genotype-derived ancestry and islet equivalents/kg, the beta-cell PGS was associated with higher insulin dose (β=0.05 units/kg/day per 1-SD, [95%CI:0.01, 0.09], p=0.016) and higher insulin dose adjusted A1c (IDAA1c) (β=0.34[95%CI:0.03, 0.67], p=0.029) 1-year post-transplant. The lipodystrophy PGS was associated with higher IDAA1c (β=0.38 [95%CI:0.06, 0.69], p=0.019) and lower fasting C-peptide (β=-0.09 [95%CI:-0.18, 0], p=0.041) at 1 year. CONCLUSIONS:T2D genetic risk is associated with diabetes prior to TPIAT, and beta cell and lipodystrophy PGS are associated with post-TPIAT diabetes outcomes. Diabetes-related genetics may influence transplantation outcomes and inform metabolic heterogeneity.

Total pancreatectomy and islet autotransplantation (TPIAT) is a specialized procedure for patients with chronic (CP) and recurrent acute pancreatitis (RAP) experiencing intractable pain and reduced quality of life. Hospitalizations for pancreatitis are common before TPIAT. However, data comparing hospitalization patterns before and after TPIAT remain limited. This multicenter, prospective observational study of TPIAT (POST) enrolled 380 patients (age 26 (15, 43 years), 34

Background. In total pancreatectomy with islet autotransplantation (TPIAT), a greater number of islets transplanted produces more favorable outcomes. We aimed to determine predictors of islet isolation outcomes. Methods. We investigated factors associated with islet isolation outcomes expressed as islet number (IN), islet equivalents (IEQ; standardized to an islet with 150 mu m diameter), IN/kg, or IEQ/kg using data from the multicenter Prospective Observational Study of TPIAT. Single-predictor linear regression was used to estimate the association of individual patient and disease characteristics with islet isolation outcomes, and augmented backward elimination was used to select variables to include in multivariable analyses. Results. In multivariable analyses, only elevated hemoglobin A1c was associated with worse outcomes for all measures (P < 0.001 for all). Total IEQ obtained for transplant was higher for participants with Hispanic ethnicity (P = 0.002) or overweight status pre-TPIAT (P < 0.001) and lower with non-White race (P = 0.03), genetic pancreatitis (P = 0.02), history of lateral pancreaticojejunostomy (P = 0.03), and presence of atrophy (P = 0.006) or ductal changes (P = 0.014) on imaging. IEQ/kg was higher in females (P = 0.01) and Hispanic participants (P = 0.046) and generally lower with older age (nonlinear association, P < 0.001) and pancreatic atrophy (P < 0.001) on imaging. Total IN and IN/kg showed trends similar, but not identical, to IEQ and IEQ/kg, respectively. Conclusions. Patient demographics and certain pancreatic disease features were associated with outcomes from islet isolation. Hemoglobin A1c before TPIAT was the metabolic testing measure most strongly associated with islet isolation results.

More than a year after the Biological License Application (BLA) approval for CellTrans, cadaveric islet transplantation remains in demise in the United States (U.S.). While the therapy is unavailable to Americans, it is already a standard of care procedure in other countries, including Canada, Australia, and many in Europe. This article discusses the challenges stemming from an outdated regulatory framework in the U.S. concerning cadaveric islet transplantation. It also presents advocacy efforts by the transplant community for appropriate regulatory adjustments and discusses future perspectives.

The REG/Reg gene locus encodes a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whether REG/Reg family members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in humans and mice, the pancreas and gut differed in REG/Reg isoform levels and preferences, with the duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, select Reg members in gut and pancreas. These Reg members had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as "inducible" and others as "constitutive". Indeed, in pancreatic ductal adenocarcinoma and pancreatitis models, only inducible Reg members were upregulated in the pancreas. While intestinal Reg expression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation of REG/Reg isoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinated Reg response.

OBJECTIVE:Total pancreatectomy with islet autotransplantation (TPIAT) may relieve pain for patients with intractable recurrent acute or chronic pancreatitis. In this first multicenter cohort study of TPIAT, we aimed to identify predictors of favorable diabetes outcomes following TPIAT to aid in surgical counseling and decision making. RESEARCH DESIGN AND METHODS:We included 384 patients (mean [SD] age 29.6 [17.1] years; 61.7% female) who underwent TPIAT and were enrolled in the National Institutes of Health-sponsored multicenter Prospective Observational Study of TPIAT (POST). Outcomes were reported for insulin use, HbA1c, and islet graft function. Univariable and multivariable modeling was performed to evaluate predictors of diabetes outcomes after TPIAT. RESULTS:At 1 year post-TPIAT, 83% of patients retained islet function (C-peptide >0.3 ng/mL), 20% were off insulin, and 60% had HbA1c <7%. Outcomes were most favorable in those with normoglycemia pre-TPIAT and in children. In multivariable analysis, insulin independence at 1 year was associated with pediatric age (odds ratio [OR] 2.3 [95% CI 1.3-4.3] vs. adults) and pretransplant HbA1c (OR 4.0 [1.7-9.1] per 1% decrease HbA1c). The odds of achieving a goal HbA1c <7% was associated with White race (OR 4.3 [1.7-11]) and pre-TPIAT HbA1c (OR 2.2 [1.1-4.3] per 1% decrease). Islet graft function was associated with pre-TPIAT fasting C-peptide (OR 2.18 [1.42-3.35] per 1 ng/mL increase) and baseline HbA1c (OR 1.89 [1.18-3] per 1% decrease). CONCLUSIONS:Patients with normoglycemia and children more often were off insulin. In multivariable models, pre-TPIAT HbA1c was strongly predictive of insulin independence, islet function, and HbA1c <7% at 1 year.