The p16INK4a tumour suppressor accumulates in many tissues as a function of advancing age. p16INK4a is an effector of senescence and a potent inhibitor of the proliferative kinase Cdk4 (ref. 6), which is essential for pancreatic beta-cell proliferation in adult mammals. Here we show that p16INK4a constrains islet proliferation and regeneration in an age-dependent manner. Expression of the p16INK4a transcript is enriched in purified islets compared with the exocrine pancreas, and islet-specific expression of p16INK4a, but not other cyclin-dependent kinase inhibitors, increases markedly with ageing. To determine the physiological significance of p16INK4a accumulation on islet function, we assessed the impact of p16INK4a deficiency and overexpression with increasing age and in the regenerative response after exposure to a specific beta-cell toxin. Transgenic mice that overexpress p16INK4a to a degree seen with ageing demonstrated decreased islet proliferation. Similarly, islet proliferation was unaffected by p16INK4a deficiency in young mice, but was relatively increased in p16(INK4a)-deficient old mice. Survival after toxin-mediated ablation of beta-cells, which requires islet proliferation, declined with advancing age; however, mice lacking p16INK4a demonstrated enhanced islet proliferation and survival after beta-cell ablation. These genetic data support the view that an age-induced increase of p16INK4a expression limits the regenerative capacity of beta-cells with ageing.

In patients with T2DM, treatment with resveratrol regulates energy expenditure through increased skeletal muscle SIRT1 and AMPK expression. These findings indicate that resveratrol may have beneficial exercise-mimetic effects in patients with T2DM.

Peritransplant intensive insulin and heparin enhances islet transplantation outcomes likely related in part to mitigation of the effects of the instant blood-mediated inflammatory reaction, combined with islet rest and avoidance of inflammation. It would be important to further investigate the effects of peritransplant insulin and heparin infusions on islet engraftment.

Percutaneous transhepatic portal access avoids surgery, but is rarely associated with bleeding or portal venous thrombosis. We herein report our large, single-center experience of percutaneous islet implantation, and evaluate risk factors of portal vein thrombosis and graft function. Prospective data was collected on 268 intraportal islet transplants (122 subjects). A portal venous Doppler ultrasound was obtained on Days 1 and 7 days posttransplant. Therapeutic heparinization, complete ablation of the portal catheter tract with Avitene paste, and limiting packed cell volume to < 5 ml completely prevented any portal thrombosis in the most recent 101 islet transplant procedures over the past 5 years. In the previous cumulative experience, partial thrombosis did not affect islet function. Standard liver volume correlated negatively (r=−0.257, P<0.001), and packed cell volume correlated positively with portal pressure rise (r=0.463, P<0.001). Overall, partial portal thrombosis occurred after 10 procedures (overall incidence 3.7%, most recent 101 patient incidence 0%). There were no cases of complete thrombosis, and no patient developed sequelae of portal hypertension. In conclusion, portal thrombosis is a preventable complication in clinical islet transplantation, provided therapeutic anticoagulation is maintained, and packed cell volume is limited to <5 ml.

This study demonstrates that needle biopsy is feasible after clinical islet transplantation but with a limited practical value because of its low islet sampling rate using current sampling and analysis methods. Both biopsy and autopsy samples demonstrated the well-preserved islet endocrine composition after transplantation and the presence of focal areas of steatosis. Islet grafts showed no or minimal immune cell infiltration, even in the case of ongoing islet loss. On the basis of the findings, possible reasons for allograft islet loss are discussed.

Summary We encountered an unexpectedly high rate of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus following islet transplantation. The goal of this retrospective chart review was to determine the frequency of ovarian cysts found on pelvic ultrasound examinations of female islet transplant recipients and to look for potential causal factors. Fifty‐seven women with a median age of 42.5 years underwent islet transplantation at the University of Alberta. Ovarian cysts were found in 31 out of 44 (70.5%) premenopausal and two out of 13 (15.4%) postmenopausal women (P = 0.001). No women using combined oral contraception developed ovarian cysts. Eight women required surgery; in four women undergoing cystectomy or unilateral oophorectomy, ovarian cysts recurred. Sirolimus withdrawal was associated with a reduction in cyst size and resolution of cysts in 80% of subjects. The risk of ovarian cysts should be discussed with female islet transplant candidates and pelvic ultrasounds performed routinely post‐transplant.

Keywords: islet transplant type 1 diabetes hypoglycemia immunosuppressionMots clés: transplantation d'îlots diabète de type 1 hypoglycémie immunosuppression a b s t r a c tThe general perception of islet transplantation among the diabetes community is somewhat negative, as insulin independence was maintained in only a small minority and there are fears about the safety of lifelong immunosuppression. There has been substantial progress in refining the islet transplant procedure to enhance its safety, reduce the toxicity of immunosuppression and improve long-term graft function. Longer-term follow-up studies have clarified the indications for islet transplantation; frequent, severe hypoglycemia, hypoglycemia unawareness and glycemic lability; facilitated informed consent and provided a framework for more realistic expectations, and suggest beneficial effects on microvascular complications. One hundred thirty-eight individuals have undergone islet transplantation at the University of Alberta over the last 12 years. Of these, 109 (79%) have full or partial graft function. Patient survival is 96% with no deaths due to transplantation. Three subjects have been hospitalized because of severe opportunistic infection and 3 have progressed to require renal replacement therapy. Current protocols are able to achieve insulin independence rates of 60% beyond 4 years. Safer and more effective islet transplantation, along with refinements in immunosuppressive therapy, make islet transplantation a more attractive option for a subset of persons with type 1 diabetes who suffer from frequent, severe hypoglycemia, lability and/or hypoglycemia unawareness, and resulting in excellent glycemic control and freedom from hypoglycemia.Ó 2012 Canadian Diabetes Association r é s u m é L'opinion générale de la communauté diabétique sur la transplantation d'îlots est quelque peu négative, comme l'insulino-indépendance est maintenue par un petit nombre seulement et qu'il y a des craintes concernant l'innocuité de l'immunosuppression permanente. Des progrès considérables quant au raffinement de la technique de transplantation d'îlots ont eu pour effet d'améliorer son innocuité, de réduire la toxicité de l'immunosuppression et d'améliorer le fonctionnement du greffon à long terme. Les études de suivi à plus long terme ont précisé les indications de la transplantation d'îlots (hypoglycémie grave et fréquente, ignorance de l'hypoglycémie et instabilité glycémique), facilité le consentement informé et fourni un cadre pour des attentes plus réalistes, et elles laissent entrevoir des effets bénéfiques concernant les complications microvasculaires. Cent trente-huit individus (138) ont subi une transplantation d'îlots à l'Université de l'Alberta au cours des douze dernières années. Parmi eux, 109 (79 %) ont un fonctionnement du greffon complet ou partiel. La survie des patients est de 96 % sans décès attribués à la transplantation. Trois (3) sujets ont été hospitalisés en raison d'infection opportuniste grave et 3 ont évolué vers la thérapie de remplacem...

Using current protocols, SII in the absence of exenatide results in impressive insulin-independence rates and the durability of insulin independence seems to be promising. However, a beneficial effect of exenatide should not be discounted until tested in randomized controlled studies.