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New Islet Cells Boost Insulin Sensitivity
October 4, 2013 (Medpage Today) – Islet cell transplantation improved insulin sensitivity in patients with long-standing type 1 diabetes, despite immunosuppressive drug regimens that have been associated with insulin resistance, researchers found.
In a small trial of 12 type 1 diabetic patients, transplantation significantly lowered mean HbA1c from 7% to 5.6% (P<0.01) and significantly increased total, hepatic, and peripheral insulin sensitivity (P<0.05 for all) -- even though all patients were on tacrolimus and sirolimus, according to Michael Rickels, MD, of the Perelman School of Medicine at the University of Pennsylvania, and colleagues.
"This is the first study to assess total body insulin sensitivity in the euglycemic clamp technique in islet transplant recipients in the modern era of glucocorticoid-free immunosuppression," they noted online in the Journal of Clinical Endocrinology & Metabolism.
The trial was "very nicely done," Gordon Weir, MD, head of islet transplantation and cell biology at Harvard's Joslin Diabetes Center told MedPage Today. Although it may have been expected that these patients had improved insulin action, Weir said the improvement was a "little less expected" given that the immunosuppressive drugs "can cause some degree of insulin resistance." "It sounds like the reversal of insulin resistance seen in diabetes won over whatever resistance came from the immunosuppressive drugs," Weir said. Indeed, immunosuppression regimens involving tacrolimus and sirolimus have been shown to induce insulin resistance in animal studies, the researchers wrote. To assess the impact on insulin sensitivity following islet cell transplant, they looked at 12 patients, mean age 46, with long-standing type 1 diabetes (mean 29 years).
These patients had intrahepatic islet transplantation, followed by low-dose tacrolimus and sirolimus immunosuppression for at least 3 months.
The researchers used a hyperinsulinemic euglycemic clamp to assess insulin sensitivity -- total body, hepatic, and peripheral -- between 6 and 7 months after the transplant. Healthy controls also had euglycemic clamping for comparison.
Transplanted patients had a significant decrease in body weight and body mass index (P<0.01 for both), and 10 of the 12 patients no longer needed insulin after the transplant.
Overall, the treatment reduced mean HbA1c from 7% to 5.6% (P<0.01), and there were significant increases in all measured forms of insulin sensitivity (P<0.05 for all):
Total: 0.11 to 0.15 dL/min*kg
Hepatic: 2.3 to 3.7 dL/min*kg
Peripheral: 0.08 to 0.12 dL/min*kg
All insulin sensitivity measures were below normal in the type 1 diabetes patients before the treatment, but were not different from normal after the transplant, Rickels and colleagues reported.
The results indicated that the improvement in total body insulin sensitivity is mediated by effects at both the liver and skeletal muscle, and that modern dosing of glucocorticoid-free immunosuppression with low-dose tacrolimus and sirolimus doesn't induce insulin resistance in these patients, the researchers concluded. "Multiple beneficial metabolic effects of islet transplantation likely work in concert to improve the impaired insulin sensitivity of type 1 diabetes," they wrote.
Weir added that it's likely that the effects of immunosuppressants on insulin resistance vary from patient to patient -- although the more important effect of islet cell transplantation is normalizing blood sugar: "That's what helps with complications."
The study was performed as a project of the Clinical Islet Transplantation Consortium, a collaborative clinical research program headquartered at the NIDDK and NIAID.
It was supported by Public Health Services Research Grants.
The researchers reported no conflicts of interest.