Dual role of interleukin-1ß in islet amyloid formation and its ß-cell toxicity: Implications for type 2 diabetes and islet transplantation.

AIMS: Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to ß-cell failure in type 2 diabetes, cultured and transplanted islets. We previously showed that biosynthetic hIAPP aggregates induce ß-cell Fas upregulation and activation of the Fas apoptotic pathway. We used cultured human and hIAPP-expressing mouse islets to investigate: (1) the role of interleukin-1ß (IL-1ß) in amyloid-induced Fas upregulation; and (2) the effects of IL-1ß-induced ß-cell dysfunction on pro-islet amyloid polypeptide (proIAPP) processing and amyloid formation. RESEARCH DESIGN AND METHODS: Human and h IAPP -expressing mouse islets were cultured to form amyloid without or with the IL-1 receptor antagonist (IL-1Ra) anakinra, in the presence or absence of recombinant IL-1ß. Human islets in which amyloid formation was prevented (amyloid inhibitor or Ad-prohIAPP-siRNA) were cultured similarly. ß-cell function, apoptosis, Fas expression, caspase-8 activation, islet IL-1ß, ß-cell area, ß-/α-cell ratio, amyloid formation, and (pro)IAPP forms were assessed. RESULTS: hIAPP aggregates were found to increase IL-1ß levels in cultured human islets that correlated with ß-cell Fas upregulation, caspase-8 activation and apoptosis, all of which were reduced by IL-1Ra treatment or prevention of amyloid formation. Moreover, IL-1Ra improved culture-induced ß-cell dysfunction and restored impaired proIAPP processing, leading to lower amyloid formation. IL-1ß treatment potentiated impaired proIAPP processing and increased amyloid formation in cultured human and h IAPP -expressing mouse islets, which were prevented by IL-1Ra. CONCLUSIONS: IL-1ß plays a dual role by: (1) mediating amyloid-induced Fas upregulation and ß-cell apoptosis; (2) inducing impaired proIAPP processing thereby potentiating amyloid formation. Blocking IL-1ß may provide a new strategy to preserve ß cells in conditions associated with islet amyloid formation.

Fluorescent cholangiography in laparoscopic cholecystectomy: the initial Canadian experience.

BACKGROUND: Bile duct injury remains a worrisome complication of laparoscopic cholecystectomy. Indocyanine Green (ICG) fluorescent cholangiography (FC) is a new approach that facilitates real-time intraoperative identification of biliary anatomy. This technology is hoped to improve the safety of dissection within Calot's triangle. METHOD: Demographics, intraoperative details, and subjective surgeon data were recorded for elective cholecystectomy cases involving ICG. Goals were to identify rates of bile duct identification, and assess the perceived benefit of the device. RESULTS: ICG was used in 12 biliary cases in Canada. Visualization rates of the cystic and common bile ducts were 100% and 83%, respectively. Also, 83% of surgeons felt that FC incorporated smoothly into the operation. No complications have been related to the technology. CONCLUSIONS: FC allows noninvasive real-time visualization of the extrahepatic biliary tree. This novel technique has received positive feedback in its initial Canadian use and will likely be a durable adjunct for minimally invasive surgery.

Percutaneous autologous pancreatic islet cell transplantation for traumatic pancreatic injury.

CONTEXT: Traumatic pancreatic injury with pancreatic duct disruption is surgically managed with at least a partial pancreatectomy, often leading to poor blood glucose control and the subsequent development of diabetes mellitus. Autologous ß-islet cell transplantation may therefore help to preserve pancreatic endocrine function. CASE DESCRIPTION: We describe 3 patients with pancreatic duct disruption from traumatic pancreatic injury who were treated with a partial pancreatectomy followed by autologous ß-islet cell transplantation via a percutaneous transhepatic approach. Immediately after trauma, 2 of the 3 patients had difficulty with glucose control that resolved after autologous ß-islet cell transplantation. At follow-up, all patients remained normoglycemic. CONCLUSION: In patients requiring partial pancreatectomy after pancreatic trauma, percutaneous transhepatic autologous ß-islet cell transplantation should be considered to minimize the risk of development of diabetes mellitus.

B7-H4 expression in normal and diseased human islet ß cells.

OBJECTIVES: B7-H4 is a negative coregulatory molecule known to be involved in immune response. We study here B7-H4 expression and its possible role in diabetes and cancer development. METHODS: Formalin-fixed, paraffin-processed pancreas samples from patients with type 1 diabetes (T1D), insulinoma, pancreatic ductal adenocarcinoma (PDAC), and normal organ donors were studied by bright-field and multifluorescence immunohistochemistry to examine B7-H4 expression and its colocalization with islet endocrine hormones. Quantitative RT-PCR and Western blot assay were used to examine B7-H4 mRNA and protein expression in the islet and exocrine tissues from normal donors and pancreatic cancer cell lines. RESULTS: B7-H4 protein expression in islet ß cells is decreased in T1D and PDAC, but increased in insulinoma patients when compared to normal controls; the changes in B7-H4 expression are concomitant with insulin expression on the islet ß cells. The insulin/B7-H4 colocalization on the ß cells, expressed in colocalization coefficient Pearson r, is also changed in these islets. CONCLUSIONS: Our observation of altered B7-H4 expression, concomitant with insulin expression, in the pancreatic islets of T1D, PDAC, and insulinoma patients when compared to normal controls suggests that B7-H4 pathway might play an important role in maintenance of ß-cell function, but its exact role remains to be explored.

Generation of transplantable Beta cells for patient-specific cell therapy.

Islet cell transplantation offers a potential cure for type 1 diabetes, but it is challenged by insufficient donor tissue and side effects of current immunosuppressive drugs. Therefore, alternative sources of insulin-producing cells and isletfriendly immunosuppression are required to increase the efficiency and safety of this procedure. Beta cells can be transdifferentiated from precursors or another heterologous (non-beta-cell) source. Recent advances in beta cell regeneration from somatic cells such as fibroblasts could circumvent the usage of immunosuppressive drugs. Therefore, generation of patient-specific beta cells provides the potential of an evolutionary treatment for patients with diabetes.

Improving islet engraftment by gene therapy.

Islet cell transplantation is currently the only feasible long-term treatment option for patients with type 1 diabetes. However, the majority of transplanted islets experience damage and apoptosis during the isolation process, a blood-mediated inflammatory microenvironment in the portal vein upon islet infusion, hypoxia induced by the low oxygenated milieu, and poor-revascularization-mediated lack of nutrients, and impaired hormone modulation in the local transplanted site. Strategies using genetic modification methods through overexpression or silencing of those proteins involved in promoting new formation of blood vessels or inhibition of apoptosis may overcome these hurdles and improve islet engraftment outcomes.

B7-H4 Pathway in Islet Transplantation and ß-Cell Replacement Therapies.

Type 1 diabetes (T1D) is a chronic autoimmune disease and characterized by absolute insulin deficiency. ß-cell replacement by islet cell transplantation has been established as a feasible treatment option for T1D. The two main obstacles after islet transplantation are alloreactive T-cell-mediated graft rejection and recurrence of autoimmune diabetes mellitus in recipients. T cells play a central role in determining the outcome of both autoimmune responses and allograft survival. B7-H4, a newly identified B7 homolog, plays a key role in maintaining T-cell homeostasis by reducing T-cell proliferation and cytokine production. The relationship between B7-H4 and allograft survival/autoimmunity has been investigated recently in both islet transplantation and the nonobese diabetic (NOD) mouse models. B7-H4 protects allograft survival and generates donor-specific tolerance. It also prevents the development of autoimmune diabetes. More importantly, B7-H4 plays an indispensable role in alloimmunity in the absence of the classic CD28/CTLA-4 : B7 pathway, suggesting a synergistic/additive effect with other agents such as CTLA-4 on inhibition of unwanted immune responses.

Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy.

BACKGROUND: The effect of islet cell transplantation (ICT) on the progression of diabetic microvascular complications is not well understood. METHODS: We have conducted a prospective, crossover, cohort study comparing ICT with intensive medical therapy on the progression of diabetic nephropathy, retinopathy, and neuropathy. RESULTS: The rate of decline in glomerular filtration rate is slower after ICT than on medical therapy. There was significantly more progression of retinopathy in medically treated patients than post-ICT. There was a nonsignificant trend for improved nerve conduction velocity post-ICT. CONCLUSIONS: ICT is associated with less progression of microvascular complications than intensive medical therapy. Multicenter, randomized trials are needed to further study the role of ICT in slowing the progression of diabetic complications.

The effect of medical therapy and islet cell transplantation on diabetic nephropathy: an interim report.

BACKGROUND: The effect of islet cell transplantation (ICT) on renal function in type 1 diabetes is uncertain and some recent studies report a significant decline in estimated glomerular filtration rate (GFR) and worsening of albuminuria. METHODS: We are conducting a prospective crossover study comparing medical treatment with islet transplantation on the progression of diabetic complications, including renal function. The primary endpoint is change in GFR measured by Tc-diethylenetriaminepentaacetate with secondary endpoints including estimated GFR and albumin excretion. RESULTS: We have followed 21 patients after islet transplantation a median of 29 months (range 13-45) and compared their results with medically treated patients followed a median 29.5 months (range 13-56). There is no difference in the rate of decline in measured GFR between medically treated patients (-0.35+/-0.89; 95% CI: -0.57 to -0.13 mL/min/month/1.73 m) and those after ICT (-0.31+/-1.18; 95% CI: -0.61 to -0.01) and neither is significantly different from that expected for the general population. The rate of decline in our estimated GFR results is lower than that reported in other studies and we did not find any worsening of albuminuria. CONCLUSIONS: We do not find evidence of worsening of renal function after islet transplantation compared with medically treated patients.

Effect of exenatide on beta cell function after islet transplantation in type 1 diabetes.

BACKGROUND: Islet transplantation can reduce or eliminate the need for insulin in patients with type 1 diabetes. Exenatide is a long acting analogue of Glucagon-like peptide-1 (GLP-1) that augments glucose induced insulin secretion, and may increase beta cell mass. We evaluated the effect of exenatide on insulin secretion after islet transplantation. METHODS: Eleven C-peptide positive islet cell recipients with elevated glucose levels were treated with exenatide for three months. Response was assessed by insulin requirements, meal tolerance tests, and hyperglycemic glucose clamps. RESULTS: Ten patients responded to exenatide. Two patients who had not restarted insulin achieved good glycemic control and one patient who had received 5500 IE/kg in first islet infusion was able to stop insulin. Seven other patients decreased their insulin dose by 39% on exenatide. Hyperglycemic clamp studies showed a rise in second phase insulin release (before exenatide: 246+/-88 pM; during exenatide: 644+/-294 pM, P<0.01). Meal tolerance studies before and one month after stopping exenatide did not show a difference in glucose or C-peptide values. Nausea and vomiting were the major side effects. CONCLUSIONS: Exenatide stimulates insulin secretion in islet transplant recipients. It reduces insulin dose in some patients and may delay the need to resume insulin in others. We did not find any evidence of a trophic effect on islets.