Pancreatic beta cell function persists in many patients with chronic type 1 diabetes, but is not dramatically improved by prolonged immunosuppression and euglycaemia from a beta cell allograft

Abstract

Aims/hypothesis: We measured serum C-peptide (at least 0.167 nmol/l) in 54 of 141 (38%) patients with chronic type 1 diabetes and sought factors that might differentiate those with detectable C-peptide from those without it. Finding no differences, and in view of the persistent anti-beta cell autoimmunity in such patients, we speculated that the immunosuppression (to weaken autoimmune attack) and euglycaemia accompanying transplant-based treatments of type 1 diabetes might promote recovery of native pancreatic beta cell function.

Methods: We performed arginine stimulation tests in three islet transplant and four whole-pancreas transplant recipients, and measured stimulated C-peptide in select venous sampling sites. On the basis of each sampling site's C-peptide concentration and kinetics, we differentiated insulin secreted from the individual's native pancreatic beta cells and that secreted from allografted beta cells.

Results: Selective venous sampling demonstrated that despite long-standing type 1 diabetes, all seven beta cell allograft recipients displayed evidence that their native pancreas secreted C-peptide. Yet even if chronic immunosuppression coupled with near normal glycaemia did improve native pancreatic C-peptide production, the magnitude of the effect was quite small.

Conclusions/interpretation: Some native pancreatic beta cell function persists even years after disease onset in most type 1 diabetic patients. However, if prolonged euglycaemia plus anti-rejection immunosuppressive therapy improves native pancreatic insulin production, the effect in our participants was small. We may have underestimated pancreatic regenerative capacity by studying only a limited number of participants or by creating conditions (e.g. high circulating insulin concentrations or immunosuppressive agents toxic to beta cells) that impair beta cell function.

Trial registration: ClinicalTrials.gov NCT00006505 NCT00246844.

Figures

Figure 1

Location of venous cannulas used for SAS and interpretation with transplanted beta cells represented by dots. In the whole pancreas transplant subjects, cannulas were placed in the hepatic, iliac, and jugular veins. Arginine stimulates both pancreata simultaneously. (A) Any C-peptide produced by the native pancreas is detected in the hepatic veins (yellow stars) before the C-peptide from the transplanted organ re-circulates (which will be detected by the jugular cannula). (B) In the case of islet transplant subjects, C-peptide found in the portal vein (green star) can be compared to the peripheral vein. Any early increase in the portal vein can be attributed to native pancreatic C-peptide production. (C) A mathematical representation to interpret the various sampling sites ([CP] = C-Peptide concentration).

Figure 2

Stimulated C-peptide responses in two insulin indepent recipients of isolated islet allografts. (A) Subject #1 displayed a significant “step-up” in portal vein C-peptide concentrations (the area shaded gray represents the excess portal vein C-peptide concentration relative to simultaneously sampled peripheral vein samples), (B) while subject #2 had nearly identical C-peptide concentrations at all time points.

Figure 3

C-peptide results from all sampling sites in pancreas allograft subjects showing that the vast majority of circulating C-peptide originated from the allograft

Figure 4

C-peptide concentration from the hepatic and peripheral sampling sites (excluding the iliac vein results shown in Figure 3 and which show C-peptide eminating from the pancreas allograft) in pancreas allograft subjects early after the arginine infusion. Each subject displays minimally elevated level C-peptide concentrations when hepatic veins samples are compared with concurrent peripheral vein blood samples.