[⁶⁸Ga]DO3A-VS-Cys⁴⁰-Exendin-4, a glucagon-like peptide 1 receptor agonist, was evaluated as a potential PET tracer for the quantitation of human islets transplanted to the liver. The short-lived PET radionuclide ⁶⁸Ga, available on a regular basis from a ⁶⁸Ge/⁶⁸Ga generator, is an attractive choice. Human C-peptide was measured to evaluate human islet function post-transplantation and prior to microPET imaging. [⁶⁸Ga]DO3A-VS-Cys⁴⁰-Exendin-4 was radiosynthesized and evaluated for PET imaging of transplanted human islets in the liver of healthy NOD/SCID mice. The biodistribution of the tracer was evaluated to determine the uptake into various organs, and qPCR of liver samples was conducted to confirm engrafted islet numbers after PET imaging. Measurement of human C-peptide indicated that higher engrafted islet mass resulted in higher human C-peptide levels in post-transplantation. The microPET imaging yielded high resolution images of liver-engrafted islets and also showed significant retention in mouse livers at 8 weeks post-transplantation. Biodistribution studies in mice revealed that liver uptake of [⁶⁸Ga]DO3A-VS-Cys⁴⁰-Exendin-4 was approximately 6-fold higher in mice that received 1000 islet equivalent (IEQ) than in non-transplanted mice. qPCR analysis of insulin expression suggested that islet engraftment numbers were close to 1000 IEQ transplanted. In conclusion, human islets transplanted into the livers of mice exhibited significant uptake of [⁶⁸Ga]DO3A-VS-Cys⁴⁰-Exendin-4 compared to the livers of untreated mice; and imaging of the mice using PET showed the human islets clearly with high contrast against liver tissue, enabling accurate quantitation of islet mass. Further validation of [⁶⁸Ga]DO3A-VS-Cys⁴⁰-Exendin-4 as an islet imaging probe for future clinical application is ongoing.

We hypothesized that DA and L-DOPA derived from nutritional tyrosine and the resultant observed postprandial plasma excursions of L-DOPA and DA might affect glucose tolerance via their ability to be taken-up by beta cells and inhibit glucose-stimulated β-cell insulin secretion.

To investigate a possible circuit between meal-stimulated 3,4-dihydroxy-L-phenylalanine (L-DOPA) and dopamine (DA) production in the GI tract and pancreatic β-cells, we: 1) mapped GI mucosal expression of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC); 2) measured L-DOPA and DA content of GI mucosal tissues following meal challenges with different L-tyrosine (TYR) content, 3) determined whether meal TYR content impacts plasma insulin and glucose excursions; and 4) characterized postprandial plasma excursions of L-DOPA and DA in response to meal tyrosine content in rodents and a population of bariatric surgery patients. Next, we characterized: 1) the metabolic transformation of TYR and L-DOPA into DA in vitro using purified islet tissue; 2) the metabolic transformation of orally administrated stable isotope labeled TYR into pancreatic DA, and 3) using a nuclear medicine technique, we studied endocrine beta cells in situ release and binding of DA in response to a glucose challenge.

We demonstrate in rodents that intestinal content and circulatory concentrations L-DOPA and DA, plasma glucose and insulin are responsive to the tyrosine (TYR) content of a test meal. Intestinal expression of two enzymes, Tyrosine hydroxylase (TH) and Aromatic Amino acid Decarboxylase (AADC), essential to the transformation of TYR to DA was mapped and the metabolism of metabolism of TYR to DA was traced in human islets and a rodent beta cell line in vitro and from gut to the pancreas in vivo. Lastly, we show that β cells secrete and bind DA in situ in response to glucose stimulation.

We provide proof-of-principle evidence for the existence of a novel postprandial circuit of glucose homeostasis dependent on nutritional tyrosine. DA and L-DOPA derived from nutritional tyrosine may serve to defend against hypoglycemia via inhibition of glucose-stimulated β-cell insulin secretion as proposed by the anti-incretin hypothesis.

•

Nutritional tyrosine is metabolized to L DOPA and DA in the foregut.

• Dopamine
• GSIS
• Glucose homeostasis
• Gut
• Tyrosine

• Animals
• Antigen-Presenting Cells/immunology
• Clinical Trials as Topic
• Cytokines/antagonists & inhibitors
• Cytokines/metabolism
• Diabetes Mellitus, Type 1/drug therapy
• Diabetes Mellitus, Type 1/immunology
• Diabetes Mellitus, Type 1/pathology
• Humans
• Hypoglycemic Agents/administration & dosage
• Hypoglycemic Agents/immunology
• Hypoglycemic Agents/pharmacology
• Immunity, Innate
• Immunologic Factors/pharmacology
• Immunomodulation/drug effects
• Immunotherapy/methods
• Insulin-Secreting Cells/drug effects
• T-Lymphocytes/drug effects
• T-Lymphocytes/immunology
• Thymus Gland/immunology
• Thymus Gland/physiopathology

• DP2 DK111913 NIDDK NIH HHS

• Diabetes
• Magnetic resonance imaging (MRI)
• Molecular imaging
• Optical imaging
• Positron emission tomography (PET)
• Single-photon emission computed tomography (SPECT)
• Theranostics
• β-Cells

• PET
• PHNO
• diabetes
• pancreas
• β-cell mass

• beta cell
• islets
• type 1 diabetes

• Animals
• Benzamides
• Contrast Media
• Islets of Langerhans/diagnostic imaging
• Islets of Langerhans Transplantation
• Lower Extremity/diagnostic imaging
• Postoperative Period
• Pyrrolidines
• Rats
• Tomography, Emission-Computed, Single-Photon/methods

β-cells, located in the islets of the pancreas, are responsible for production and secretion of insulin and play a crucial role in blood sugar regulation. Pathologic β-cells often cause serious medical conditions affecting blood glucose level, which severely impact life quality and are life-threatening if untreated. With 347 million patients, diabetes is one of the most prevalent diseases, and will continue to be one of the largest socioeconomic challenges in the future. The diagnosis still relies mainly on indirect methods like blood sugar measurements. A non-invasive diagnostic imaging modality would allow direct evaluation of β-cell mass and would be a huge step towards personalized medicine. Hyperinsulinism is another serious condition caused by β-cells that excessively secrete insulin, like for instance β-cell hyperplasia and insulinomas. Treatment options with drugs are normally not curative, whereas curative procedures usually consist of the resection of affected regions for which, however, an exact localization of the foci is necessary. In this review, we describe potential tracers under development for targeting β-cells with focus on radiotracers for PET and SPECT imaging, which allow the non-invasive visualization of β-cells. We discuss either the advantages or limitations for the various tracers and modalities. This article concludes with an outlook on future developments and discuss the potential of new imaging probes including dual probes that utilize functionalities for both a radioactive and optical moiety as well as for theranostic applications.

• Imaging
• MRI
• Optical imaging
• PET/SPECT
• Pancreas
• β-cells

• Adipose Tissue, Brown/diagnostic imaging
• Adipose Tissue, Brown/metabolism
• Adipose Tissue, Brown/pathology
• Adipose Tissue, Brown/radiation effects
• Animals
• Diabetes Mellitus, Experimental/diagnostic imaging
• Diabetes Mellitus, Experimental/pathology
• Fluorodeoxyglucose F18/chemistry
• Male
• Positron-Emission Tomography
• Rats
• Streptozocin/toxicity
• Tomography, X-Ray Computed

• R21 DK092917 NIDDK NIH HHS
• RC1 DK087352 NIDDK NIH HHS

Imaging of rat pancreatic β-cells using cubic bicontinuous liquid crystalline nanoparticles loaded with the TB139 fluorescent dye.

Medical imaging technologies are acquiring an increasing relevance to assist clinicians in diagnosis and to guide management and therapeutic treatment of patients, thanks to their non invasive and high resolution properties. Computed tomography, magnetic resonance imaging, and ultrasonography are the most used imaging modalities to provide detailed morphological reconstructions of tissues and organs. In addition, the use of contrast dyes or radionuclide-labeled tracers permits to get functional and quantitative information about tissue physiology and metabolism in normal and disease state. In recent years, the development of multimodal and hydrid imaging techniques is coming to be the new frontier of medical imaging for the possibility to overcome limitations of single modalities and to obtain physiological and pathophysiological measurements within an accurate anatomical framework. Moreover, the employment of molecular probes, such as ligands or antibodies, allows a selective in vivo targeting of biomolecules involved in specific cellular processes, so expanding the potentialities of imaging techniques for clinical and research applications. This review is aimed to give a survey of characteristics of main diagnostic non-invasive imaging techniques. Current clinical appliances and future perspectives of imaging in the diagnostic and prognostic assessment of diabetic complications affecting different organ systems will be particularly addressed.

• Medical non-invasive imaging
• Diabetes
• Diabetic complications
• Molecular imaging
• Multimodal imaging
• Hybrid scanners

• (11)C-fallypride
• (18)F-fallypride
• Dopamine receptors
• PET
• Spinal cord