OBJECTIVE—With increasing emphasis on the recognition of the metabolic syndrome and early type 2 diabetes, a clinically useful measure of insulin resistance is desirable. The purpose of this study was to evaluate whether an index of glucose metabolism, as measured by 13CO2 generation from ingested [13C]glucose, would correlate with indexes from the hyperinsulinemic-euglycemic clamp. RESEARCH DESIGN AND METHODS—A total of 26 subjects with varying degrees of insulin sensitivity underwent both the [13C]glucose breath test and the hyperinsulinemic-euglycemic clamp. Results from the [13C]glucose breath test were compared with measures of insulin sensitivity from the glucose clamp as well as with other commonly used indexes of insulin sensitivity. RESULTS—There was a strong correlation between the [13C]glucose breath test result and the glucose disposal rate (r = 0.69, P < 0.0001) and insulin sensitivity index (r = 0.69, P < 0.0001) from the insulin clamp. The magnitude of these correlations compared favorably with QUICKI and were superior to the homeostasis model assessment. CONCLUSIONS—The [13C]glucose breath test may provide a useful noninvasive assessment of insulin sensitivity.
Background. Pancreas transplantation has been shown to fully restore glucagon response and partially restore epinephrine response to hypoglycemia during the first few years after transplantation in patients with type 1 diabetes. However, prior studies have not examined hypoglycemic counterregulation in any pancreas transplant recipient of more than 6 years' duration. Methods. To determine whether restoration of hypoglycemic counterregulation is maintained over a prolonged period after transplantation, we studied counterregulatory responses and symptom recognition in two groups of pancreas transplant recipients using a stepped hypoglycemic, hyperinsulinemic clamp. Group 1 consisted of 11 successful transplant recipients of 11 to 19 years' duration (mean±SE, 13.9±0.7 years). Group 2A consisted of seven successful pancreas transplant recipients of 5 to 11 years' duration (mean±SE, 8.7±0.9 years) who had been studied approximately 5 years earlier using the same stepped, hypoglycemic clamp technique. Results. Both groups had significant rises in plasma glucagon during the hypoglycemic clamp similar to that seen in short-term recipients and normal controls. Both groups also had significant increases in plasma epinephrine responses similar to that seen in short-term transplant recipients but less than that of normal control subjects. The mean symptom scores of group 1 were significantly less than those of the control group at glucose levels of 60 and 50 mg/dL but not at 40 mg/dL. The mean symptom scores of group 2A were not significantly different than that of control subjects. Conclusion. These results indicate that the restoration of hypoglycemic counterregulation by pancreas transplantation remains stable in successful pancreas transplant recipients for up to 19 years after transplantation.
Despite significant improvements in islet transplantation, long-term graft function is still not optimal. It is likely that both immune and nonimmune factors are involved in the deterioration of islet function over time. Historically, the pretransplant T-cell crossmatch and antibody screening were done by anti-human globulin—complement-dependent cytotoxicity (AHG-CDC). Class II antibodies were not evaluated. In 2003, we introduced solid-phase antibody screening using flow-based beads and flow crossmatching. We were interested to know whether pretransplant human leukocyte antigen (HLA) antibodies or a positive flow crossmatch impacted islet function post-transplant. A total of 152 islet transplants was performed in 81 patients. Islet function was determined by a positive C-peptide. Results were analyzed by procedure. Class I and class II panel reactive antibody (PRA) > 15% and donor-specific antibodies (DSA) were associated with a reduced C-peptide survival (p < 0.0001 and p < 0.0001, respectively). A positive T- and or B-cell crossmatch alone was not. Pretransplant HLA antibodies detectable by flow beads are associated with reduced graft survival. This suggests that the sirolimus and low-dose tacrolimus-based immunosuppression may not control the alloimmune response in this presensitized population and individuals with a PRA > 15% may require more aggressive inductive and maintenance immunosuppression, or represent a group that may not benefit from islet transplantation.
Pancreatic islet transplantation can provide insulin independence and near normal glucose control in selected patients with type 1 diabetes mellitus. However, in most cases, achieving insulin independence necessitates the use of at least two donor pancreases per recipient and the rate of insulin independence may decline after transplantation. To better understand the fate of transplanted islets and the relationship between transplanted islet mass, graft function, and overall glucose homeostasis, an accurate and reproducible method of imaging islets in vivo is needed.Recent advances in noninvasive imaging techniques such as magnetic resonance imaging, positron emission tomography, and other imaging modalities show great promise as potential tools to monitor islet number, mass, and function in the clinical setting. A recent international workshop, "Imaging the Pancreatic Beta Cell," sponsored by the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Juvenile Diabetes Research Foundation International focused on these emerging efforts to develop novel ways of imaging pancreatic beta cells in vivo.Potential clinically applicable techniques include the use of directed magnetic resonance contrast agents such as lanthanides (Ln(3+)) and manganese (Mn(2+)) or magnetic resonance imaging probes such as superparamagnetic iron oxide nanoparticles. Potential techniques for positron emission tomography imaging include the use of beta cell-specific antibodies, or pharmacologic agents such as glyburide analogs, or d-mannoheptulose. Optical imaging techniques are also being used to evaluate various aspects of beta cell metabolism including intracellular Ca(2+) flux, glucokinase activity, and insulin granular exocytosis.The consensus among investigators at the imaging workshop was that an accurate and reproducible in vivo measure of functional islet mass is critically needed to further the strides that have been made in both islet transplantation and diabetes research as a whole. Such measures would potentially allow the assessment of islet engraftment and the early recognition of graft loss, leading to greater improvements in islet graft survival and function.
Thompson, D. M.; Ao, Z.; Meloche, M.; Shapiro, J.; Keown, P. A.; Paty, B.; Fung, M.; Ho, S.; Almehthel, M.; Kondi, J.; Meneilly, G.; Kozak, S. E.; Tong, S.; Trinh, M.; Warnock, G. Author Information
Sequential pancreatic islet transplantation via the portal vein has led to insulin independence in patients with type 1 diabetes. Complications associated with the injection of islets into the portal vein have been reported; therefore, in this study we sought to further characterize changes in portal venous pressure associated with islet infusion.Pre- and posttransplant portal venous pressures were recorded in 50 consecutive transplant procedures in 26 patients receiving highly purified, heparinized allogeneic islet preparations via a radiologically placed portal venous cannula. Doppler ultrasound scans of the portal vein were completed within 24 hr of transplantation.Posttransplant portal vein pressures rose significantly with sequential transplantation (12.4 mm Hg vs. 17.3 mm Hg, P <0.05). Portal pressure change correlated significantly with islet packed cell volume (r =0.66, P <0.001) and also with the number of islets transplanted ( r=0.49, P <0.001). Segmental portal vein thrombosis was radiologically detected after two procedures (4%).Multiple sequential islet transplants can be safely performed via the portal vein, provided that care is taken with islet purification and attention is paid to portal venous monitoring.
Diabetes mellitus prevalence is increasing worldwide. Type 1 diabetes (T1DM), which is caused mainly by autoimmune destruction of beta cells, accounts for approximately 5–10 % of all diabetes. Intensive glycemic control has been shown to reduce complications of T1DM. However, this has been difficult to achieve and is usually associated with frequent hypoglycemia. Islet transplantation (IT) has emerged as an acceptable method for the treatment of patients with T1DM who suffer for frequent severe hypoglycemia and/or glycemic lability. Although initial success was limited, improvement in IT has been observed over the last 15 years. The 5-year insulin independence rate approaches 30–50 % in some experienced centers. Even without achieving insulin independence, IT has significant benefits including prevention of hypoglycemia, stabilization of glycemic control, reduction in some complications of diabetes, and improvement in quality of life. Here, we provide a brief review on IT including its history, selection of IT candidates, description, and complications of the procedure and outcomes.
