Positron Emission Tomography and Magnetic Resonance Techniques in Diabetes

In order to further advance the field of diabetes research there is a great need for establishing validated non-invasive quantitative techniques to study the pancreas and other tissues of importance for blood glucose regulation. The general aim of this thesis was to explore magnetic resonance techniques and positron emission tomography as such tools. In paper I pancreatic perfusion under basal conditions and in response to glucose in nondiabetic and type 1 diabetic individuals was studied with [15O]H2O PET/CT. Individuals with type 1 diabetes were found to have reduced basal pancreatic perfusion and a severely impaired pancreatic and splanchnic perfusion response to intravenous glucose stimulation. In paper II four groups of subjects at different stages of type 2 diabetes development and a control group of individuals without diabetes were examined with PET/CT and MRI. The [11C]5-HTP uptake in pancreas was hypothesized to correlate with remaining functional capacity of the β-cells. The progressive loss of β-cell function indicated by metabolic testing was not mirrored by a decrease in [11C]5-HTP tracer accumulation in the pancreas. This provides evidence of retained islet mass despite decreased β-cell function, indicating that β-cell dysfunction or dedifferentiation, and not necessarily endocrine cell loss, constitutes a major cause of β-cell failure in type 2 diabetes. In paper III the feasibility of using ex-vivo MR spectroscopy for assessment of viability of human pancreas grafts prior to transplantation was studied. It was found that 31P-MRS may provide quantitative parameters for evaluating graft viability ex vivo, and is a promising tool for objective non-invasive assessment of the quality of human pancreas grafts. In paper IV the Imiomics method for automatic image analysis was validated in whole-body [18F]-FDG PET/MR images in subjects with varying degree of insulin resistance. Imiomics was found to provide association screening and timesaving analysis of whole-body data and detected differences in glucose uptake and tissue composition between subjects on voxel-level. However, it did not show complete correlation with traditional volume of interest based tissue analysis in a small cohort

Positron Emission Tomography and Magnetic Resonance Techniques in Diabetes

In order to further advance the field of diabetes research there is a great need for establishing validated non-invasive quantitative techniques to study the pancreas and other tissues of importance for blood glucose regulation. The general aim of this thesis was to explore magnetic resonance techniques and positron emission tomography as such tools. In paper I pancreatic perfusion under basal conditions and in response to glucose in nondiabetic and type 1 diabetic individuals was studied with [15O]H2O PET/CT. Individuals with type 1 diabetes were found to have reduced basal pancreatic perfusion and a severely impaired pancreatic and splanchnic perfusion response to intravenous glucose stimulation. In paper II four groups of subjects at different stages of type 2 diabetes development and a control group of individuals without diabetes were examined with PET/CT and MRI. The [11C]5-HTP uptake in pancreas was hypothesized to correlate with remaining functional capacity of the β-cells. The progressive loss of β-cell function indicated by metabolic testing was not mirrored by a decrease in [11C]5-HTP tracer accumulation in the pancreas. This provides evidence of retained islet mass despite decreased β-cell function, indicating that β-cell dysfunction or dedifferentiation, and not necessarily endocrine cell loss, constitutes a major cause of β-cell failure in type 2 diabetes. In paper III the feasibility of using ex-vivo MR spectroscopy for assessment of viability of human pancreas grafts prior to transplantation was studied. It was found that 31P-MRS may provide quantitative parameters for evaluating graft viability ex vivo, and is a promising tool for objective non-invasive assessment of the quality of human pancreas grafts. In paper IV the Imiomics method for automatic image analysis was validated in whole-body [18F]-FDG PET/MR images in subjects with varying degree of insulin resistance. Imiomics was found to provide association screening and timesaving analysis of whole-body data and detected differences in glucose uptake and tissue composition between subjects on voxel-level. However, it did not show complete correlation with traditional volume of interest based tissue analysis in a small cohort

Whole-body MRI including diffusion-weighted MRI compared with 5-HTP PET/CT in the detection of neuroendocrine tumors

Aim: We wanted to explore if whole-body magnetic resonance imaging (MRI) including diffusion-weighted (DW) and liver-specific contrast agent-enhanced imaging could be valuable in lesion detection of neuroendocrine tumors (NET). [11C]-5-Hydroxytryptophan positron emission tomography/computed tomography (5-HTP PET/CT) was used for comparison. Materials and methods: Twenty-one patients with NET were investigated with whole-body MRI, including DW imaging (DWI) and contrast-enhanced imaging of the liver, and whole-body 5-HTP PET/CT. Seven additional patients underwent upper abdomen MRI including DWI, liver-specific contrast agent-enhanced imaging, and 5-HTP PET/CT. Results: There was a patient-based concordance of 61% and a lesion-based concordance of 53% between the modalities. MRI showed good concordance with PET in detecting bone metastases but was less sensitive in detecting metastases in mediastinal lymph nodes. MRI detected more liver metastases than 5-HTP PET/CT. Conclusion: Whole-body MRI with DWI did not detect all NET lesions found with whole-body 5-HTP PET/CT. Our findings indicate that MRI of the liver including liver-specific contrast agent-enhanced imaging and DWI could be a useful complement to whole-body 5-HTP PET/CT

Pancreatic perfusion and its response to glucose as measured by simultaneous PET/MRI

AIMS: Perfusion of the pancreas and the islets of Langerhans is sensitive to physiological stimuli and is dysregulated in metabolic disease. Pancreatic perfusion can be assessed by both positron emission tomography (PET) and magnetic resonance imaging (MRI), but the methods have not been directly compared or benchmarked against the gold-standard microsphere technique. METHODS: Pigs (n = 4) were examined by [15O]H2O PET and intravoxel incoherent motion (IVIM) MRI technique simultaneously using a hybrid PET/MRI scanner. The pancreatic perfusion was measured both at basal conditions and after intravenous (IV) administration of up to 0.5 g/kg glucose. RESULTS: Pancreatic perfusion increased by 35%, 157%, and 29% after IV 0.5 g/kg glucose compared to during basal conditions, as assessed by [15O]H2O PET, IVIM MRI, and microspheres, respectively. There was a correlation between pancreatic perfusion as assessed by [15O]H2O PET and IVIM MRI (r = 0.81, R2 = 0.65, p < 0.01). The absolute quantification of pancreatic perfusion (ml/min/g) by [15O]H2O PET was within a 15% error of margin of the microsphere technique. CONCLUSION: Pancreatic perfusion by [15O]H2O PET was in agreement with the microsphere technique assessment. The IVIM MRI method has the potential to replace [15O]H2O PET if the pancreatic perfusion is sufficiently large, but not when absolute quantitation is required

Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus

Macroencapsulation devices provide the dual possibility to immunoprotect transplanted cells while also being retrievable; the latter bearing importance for safety in future trials with stem-cell derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets to patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155000-180000 IEQ (i.e. 1800-4600 IEQ per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited.De två första författarna delar förstaförfattarskapet.</p