The team, led by Michael Rickels and including first author Juan Alvarez-Dominguez, examined peri-transplant metabolic outcomes in all eleven recipients who received allogeneic islet transplantation between 2008 and 2012. The cohort, four men and seven women with a median age of 49 years and a median diabetes duration of 34 years, received a median of 7,879 islet equivalents per kilogram of body weight, with each infusion drawn from a single donor pancreas. Immunosuppression followed the CIT07 regimen, combining anti-thymocyte globulin and etanercept for induction with low-dose tacrolimus and sirolimus for maintenance. Blood glucose was monitored more than four times daily, and insulin requirements, glycemic lability, and endogenous insulin secretion were tracked systematically through the first 75 days after transplant.

The peri-transplant management strategy centers on a concept the authors call islet rest. After islets are infused into the portal vein, they must revascularize, arterialize, and secure adequate oxygen supply before they can be asked to carry a full secretory load. To protect them during this vulnerable window, clinicians administer intensive exogenous insulin with the goal of near-normoglycemia, targeting fasting and pre-prandial glucose values of 80 to 120 mg/dL and post-prandial values below 180 mg/dL for at least several weeks. This approach shields the newly delivered cells from glucose toxicity while minimizing the demand placed on them to secrete insulin. Yet because primary islets isolated from deceased donors are developmentally and functionally mature, they continue to sense glucose and release insulin immediately, even under the stress of isolation and the relatively hypoxic environment of the transplant site.

The data show that this immediate function translates into rapid clinical benefit. Median blood glucose fell from 148 mg/dL before transplant to 104 mg/dL afterward, and glycemic lability, a measure of temporal glucose variability, dropped from 14.5 to 1.0 (mmol/L)²/hour, both within the first week following infusion. Insulin requirements declined from a median of 27 units per day to 12 units per day, falling week by week until they plateaued between weeks 4 and 8 at less than half the pre-transplant dose. Between days 56 and 75, all eleven recipients tapered off exogenous insulin entirely, and although blood glucose rose modestly during this interval, all met glucose targets with minimal variability and completed a mixed-meal tolerance test at day 75 without any exogenous insulin support.

Perhaps the most striking evidence of early graft function comes from C-peptide measurements, which serve as a proxy for endogenous insulin secretion. Before transplantation, fasting and stimulated C-peptide were undetectable in all recipients, below 0.05 ng/mL, consistent with long-standing type 1 diabetes. By day 3 after infusion, C-peptide was already detectable at clinically meaningful concentrations, and it rose progressively through the day 75 mixed-meal tolerance test. At that point, all recipients had fasting glucose below 120 mg/dL. Seven of the eleven achieved a 90-minute post-meal glucose below 180 mg/dL, while the remaining four qualified for a second islet infusion. All seven recipients with adequate post-meal glucose control had stimulated C-peptide levels above the 2.93 ng/mL threshold identified by the Collaborative Islet Transplant Registry as predictive of insulin independence, and among the four who needed a second infusion, two fell below and two above that same threshold.

The authors emphasize that these early metabolic effects occur despite the deliberate suppression of secretory demand through insulin therapy. The gradual increases in fasting and stimulated C-peptide indicate that graft oxygenation and functionality improve over time, while the immediate contribution to glucose control demonstrates that mature primary islets do not require a prolonged maturation period to become metabolically active. Previous work from the same cohort showed that full graft function was established by day 75, with beta-cell secretory capacity measured by glucose-potentiated arginine testing remaining comparable between day 75 and day 365. The day 75 C-peptide values also align with those identified through long-term registry follow-up as predicting optimal outcomes for islet transplant alone recipients.

This rapid timeline stands in sharp contrast to what has been observed with stem cell-derived islets, the emerging alternative to donor pancreases that could one day eliminate the constraints of organ supply. Unlike primary islets, SC-islets are molecularly and functionally immature, lacking the precision, kinetics, and extent of insulin release characteristic of adult islets. In a recent clinical trial of intraportally delivered SC-islets, recipients needed more than 120 days on average to reduce exogenous insulin requirements by 50 percent, compared with roughly 21 days for primary islet recipients in the CIT07 cohort. The authors attribute this more than fivefold delay to a genuine maturation process that SC-islets must undergo in vivo, gaining glucose-dependent insulin secretion beyond the initial engraftment period, rather than to an insufficient transplanted cell mass.

Notably, the SC-islet trial used the same dosing logic, delivery route, and immunosuppression protocol as CIT07, and its ultimate outcomes were comparable. Ten of twelve SC-islet recipients eventually became insulin-independent with a single infusion, similar to the seven of eleven in the primary islet cohort. Because achieving insulin independence supports the establishment of a reserve capacity for insulin secretion, the authors argue that delayed functional maturation, not inadequate engrafted mass, explains the slower glucose improvement. This distinction matters enormously for how SC-islet products are evaluated, since the tools used to assess primary islet graft function in the first days and weeks may not be interpretable when applied to a product that is still maturing.

The practical implications extend to clinical decision-making and regulatory science alike. In primary islet transplantation, primary graft non-function, instant blood-mediated inflammatory response, and acute rejection can all be detected through metabolic function testing within the first days to weeks after infusion. For SC-islets, these same mechanisms of graft failure may go unidentified while clinicians wait for in vivo maturation to unfold, delaying the ability to judge whether a given dose was adequate, whether engraftment succeeded, and whether immune evasion strategies are working. The authors suggest that early metabolic control outcomes from primary islet transplantation can serve as functional benchmarks for a fully mature SC-islet product when assessing longer-term outcomes, and that future advances enabling earlier functional assessment will help align expectations with evolving regulatory standards.

As stem cell-derived islet products advance toward broader clinical testing, the timeline documented here provides a reference point against which their performance can be measured. The message from the CIT07 cohort is unambiguous: mature islets act fast, and the speed of metabolic rescue is itself a signal of graft quality. Bridging the gap between that standard and the slower maturation of stem cell-derived alternatives is now one of the central challenges in the field of beta-cell replacement therapy.

Subject of Research: Early metabolic control timeline after primary islet transplantation and its implications for stem cell-derived islet product development in type 1 diabetes

Article Title: Rapid metabolic control after primary islet transplantation: relevance for stem cell-derived islet product development

Article References: Rapid metabolic control after primary islet transplantation: relevance for stem cell-derived islet product development. (n.d.). https://doi.org/10.3389/ti.2026.17176

Image Credits: AI Generated

DOI: 10.3389/ti.2026.17176

Keywords: islet transplantation, type 1 diabetes, stem cell-derived islets, C-peptide, glucose control, beta-cell replacement, CIT07 protocol, insulin independence, Transplant International, islet rest, glycemic lability, functional maturation