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6 results on '"Kirsi, Mikkola"'

1. Metformin increases the uptake of glucose into the gut from the circulation in high-fat diet-fed male mice, which is enhanced by a reduction in whole-body Slc2a2 expression

Author

Nicola Morrice, Susanne Vainio, Kirsi Mikkola, Lidy van Aalten, Jennifer R. Gallagher, Michael L.J. Ashford, Alison D. McNeilly, Rory J. McCrimmon, Alexandra Grosfeld, Patricia Serradas, Jukka Koffert, Ewan R. Pearson, Pirjo Nuutila, and Calum Sutherland

Subjects
Diabetes, Metformin, Slc2a2, Glucose-uptake, [18F]FDG-PET, Internal medicine, RC31-1245
Abstract

Objectives: Metformin is the first line therapy recommended for type 2 diabetes. However, the precise mechanism of action remains unclear and up to a quarter of patients show some degree of intolerance to the drug, with a similar number showing poor response to treatment, limiting its effectiveness. A better understanding of the mechanism of action of metformin may improve its clinical use. SLC2A2 (GLUT2) is a transmembrane facilitated glucose transporter, with important roles in the liver, gut and pancreas. Our group previously identified single nucleotide polymorphisms in the human SLC2A2 gene, which were associated with reduced transporter expression and an improved response to metformin treatment. The aims of this study were to model Slc2a2 deficiency and measure the impact on glucose homoeostasis and metformin response in mice. Methods: We performed extensive metabolic phenotyping and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG)-positron emission tomography (PET) analysis of gut glucose uptake in high-fat diet-fed (HFD) mice with whole-body reduced Slc2a2 (Slc2a2+/−) and intestinal Slc2a2 KO, to assess the impact of metformin treatment. Results: Slc2a2 partial deficiency had no major impact on body weight and insulin sensitivity, however mice with whole-body reduced Slc2a2 expression (Slc2a2+/−) developed an age-related decline in glucose homoeostasis (as measured by glucose tolerance test) compared to wild-type (Slc2a2+/+) littermates. Glucose uptake into the gut from the circulation was enhanced by metformin exposure in Slc2a2+/+ animals fed HFD and this action of the drug was significantly higher in Slc2a2+/− animals. However, there was no effect of specifically knocking-out Slc2a2 in the mouse intestinal epithelial cells. Conclusions: Overall, this work identifies a differential metformin response, dependent on expression of the SLC2A2 glucose transporter, and also adds to the growing evidence that metformin efficacy includes modifying glucose transport in the gut. We also describe a novel and important role for this transporter in maintaining efficient glucose homoeostasis during ageing.

Published
2023
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3. Synthesis and preclinical characterization of [Cu-64]NODAGA-MAL-exendin-4 with a N-epsilon-maleoyl-l-lysyl-glycine linkage

Author

Joern Schlesinger, Tamiko Ishizu, Johan Rajander, Veronica Fagerholm, Kirsi Mikkola, Viki-Veikko Elomaa, Cheng-Bin Yim, Olof Solin, Pirjo Nuutila, and Anne Roivainen

Subjects
Male, endocrine system, Cancer Research, Glycine, Peptide, Chemistry Techniques, Synthetic, Acetates, ta3111, complex mixtures, 030218 nuclear medicine & medical imaging, Heterocyclic Compounds, 1-Ring, 03 medical and health sciences, fluids and secretions, 0302 clinical medicine, Drug Stability, In vivo, medicine, Animals, Humans, Radiology, Nuclear Medicine and imaging, chemistry.chemical_classification, Kidney, Venoms, digestive, oral, and skin physiology, Radiochemistry, In vitro, Rats, Amino acid, Kinetics, medicine.anatomical_structure, chemistry, Biochemistry, Isotope Labeling, Positron-Emission Tomography, 030220 oncology & carcinogenesis, Lipophilicity, Autoradiography, Exenatide, Molecular Medicine, Copper-64, Peptides, Hydrophobic and Hydrophilic Interactions
Abstract

Introduction Renal localization of high radioactivity levels during targeted imaging compromises tissue visualization in the kidney region and limits diagnostic accuracy. Radioiodinated antibody fragments with a renal enzyme-cleavable N e -maleoyl-l-lysyl-glycine (MAL) linkage demonstrated low renal radioactivity levels in mice, from early postinjection times. This study tested the hypothesis whether a 64 Cu-labeled NODAGA-exendin-4 peptide with a MAL linkage ([ 64 Cu]NODAGA-MAL-exendin-4) could decrease kidney radioactivity levels in rats, compared to a [ 64 Cu]NODAGA-exendin-4 reference, without impairing the radioactivity levels in the target tissue. Methods NODAGA-MAL-exendin-4 was synthesized in a two-phase approach using solid support to prepare maleoyl-derivatized NODAGA followed by Michael addition to cysteine-derivatized exendin-4 in solution. Radiolabeling was performed in buffered aqua with [ 64 Cu]CuCl 2 , which was produced via the 64 Ni(p,n) 64 Cu nuclear reaction. The in vitro and in vivo stability, lipophilicity, and distribution kinetics in major rat organs for [ 64 Cu]NODAGA-MAL-exendin-4 were studied and compared to [ 64 Cu]NODAGA-exendin-4. Labeling of pancreatic islets was assessed using autoradiography. Results NODAGA-MAL-exendin-4 was synthesized, with an overall yield of 9%, and radiolabeled with 64 Cu with high specific radioactivity. Serum incubation studies showed high stability for [ 64 Cu]NODAGA-MAL-exendin-4. Similar tissue distribution kinetics was observed for [ 64 Cu]NODAGA-MAL-exendin-4 and [ 64 Cu]NODAGA-exendin-4, with high kidney radioactivity levels. Conclusions The incorporated MAL linkage in [ 64 Cu]NODAGA-MAL-exendin-4 was unable to reduce kidney radioactivity levels, compared to [ 64 Cu]NODAGA-exendin-4. The applicability of metabolizable linkages in the design of kidney-saving exendin-4 analogs requires further investigation.

Published
2013

4. Assessment of Islet Specificity of Dihydrotetrabenazine Radiotracer Binding in Rat Pancreas and Human Pancreas

Author

Veronica Fagerholm, K. Någren, Saila Kauhanen, Eveliina Arponen, Pirjo Nuutila, Olof Solin, Kirsi Mikkola, Merja Haaparanta, and Tamiko Ishizu

Subjects
Male, Biodistribution, medicine.medical_specialty, Tetrabenazine, Vesicular monoamine transporter 2, Binding, Competitive, 030218 nuclear medicine & medical imaging, Dihydrotetrabenazine, Islets of Langerhans, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Diabetes Mellitus, medicine, Animals, Humans, Radiology, Nuclear Medicine and imaging, Radioactive Tracers, 030304 developmental biology, 0303 health sciences, geography, geography.geographical_feature_category, biology, Pancreatic islets, Middle Aged, Islet, In vitro, Rats, Dissociation constant, medicine.anatomical_structure, Endocrinology, chemistry, Organ Specificity, Vesicular Monoamine Transport Proteins, biology.protein, Autoradiography, Cattle, Female, Pancreas, Protein Binding
Abstract

Vesicular monoamine transporter 2 (VMAT2) is a putative molecular target for the quantitative imaging of pancreatic beta-cell mass by PET. The VMAT2 PET tracer (11)C-dihydrotetrabenazine ((11)C-DTBZ) exhibits high pancreatic uptake that is reduced in type 1 diabetes. The aim of this study was to assess the islet and VMAT2 specificity of DTBZ binding in the pancreas.The biodistribution of (11)C-DTBZ in rats was determined 10 and 60 min after injection. The localization of DTBZ radioactivity in rat and human pancreatic tissue sections was investigated by autoradiography. Saturation and competition binding assays were performed with (3)H-DTBZ and sections of rat pancreatic and control tissues. The binding of (11)C-DTBZ in pancreatic sections from rats with streptozotocin-induced diabetes was compared with that in control rats.The values for the pancreatic uptake of (11)C-DTBZ (percentage injected dose per gram of tissue) were 3.0 at 10 min and 2.7 at 60 min. At 10 min, pancreatic radioactivity was heterogeneously distributed, with higher levels toward the head of the pancreas (head-to-tail ratio, 1.7). No such gradient was observed in pancreatic sections incubated with (11)C-DTBZ and (3)H-DTBZ in vitro. In rats, (11)C-DTBZ and (3)H-DTBZ binding in pancreatic islets did not exceed binding in the exocrine pancreas. Saturable (3)H-DTBZ binding was observed in the rat brain striatum (dissociation constant [K(d)], 1.3 nM) and the bovine adrenal medulla (K(d), 3.3 nM), whereas in the rat pancreas, (3)H-DTBZ binding was nonsaturable. Competition binding with (3)H-DTBZ and VMAT2 antagonists also indicated that DTBZ binding in the rat pancreas was nonspecific and did not represent binding to VMAT2. Nonspecific pancreatic (11)C-DTBZ binding was lower in rats with streptozotocin-induced diabetes than in control rats. In sections of human pancreas, a subset of pancreatic islets were weakly but VMAT2-specifically labeled with (3)H-DTBZ.The results showed that the pancreatic uptake of (11)C-DTBZ is mainly due to nonspecific binding in the exocrine pancreas and suggested that the reduction in pancreatic (11)C-DTBZ binding observed in type 1 diabetes is not specific for the loss of beta-cell mass.

Published
2010
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5. Cu- and Ga-Labelled [Nle,Lys(Ahx-NODAGA)NH]-Exendin-4 for Pancreatic Beta Cell Imaging in Rats.

Author

Kirsi, Mikkola, Cheng-Bin, Yim, Veronica, Fagerholm, Tamiko, Ishizu, Viki-Veikko, Elomaa, Johan, Rajander, Jori, Jurttila, Tiina, Saanijoki, Tuula, Tolvanen, Marko, Tirri, Eleni, Gourni, Martin, Béhé, Martin, Gotthardt, Claude, Reubi, Helmut, Mäcke, Anne, Roivainen, Olof, Solin, and Pirjo, Nuutila

Subjects
GLUCAGON-like peptide-1 receptor, PANCREATIC beta cells, MOLECULAR biology, GALLIUM, COPPER, LIPOPHILICITY, LABORATORY rats
Abstract

Purpose: Glucagon-like peptide-1 receptor (GLP-1R) is a molecular target for imaging of pancreatic beta cells. We compared the ability of [Nle,Lys(Ahx-NODAGA-Cu)NH]-exendin-4 ([Cu]NODAGA-exendin-4) and [Nle,Lys(Ahx-NODAGA-Ga)NH]-exendin-4 ([Ga]NODAGA-exendin-4) to detect native pancreatic islets in rodents. Procedures: The stability, lipophilicity and affinity of the radiotracers to the GLP-1R were determined in vitro. The biodistribution of the tracers was assessed using autoradiography, ex vivo biodistribution and PET imaging. Estimates for human radiation dosimetry were calculated. Results: We found GLP-1R-specific labelling of pancreatic islets. However, the pancreas could not be visualised in PET images. The highest uptake of the tracers was observed in the kidneys. Effective dose estimates for [Cu]NODAGA-exendin-4 and [Ga]NODAGA-exendin-4 were 0.144 and 0.012 mSv/MBq, respectively. Conclusion: [Cu]NODAGA-exendin-4 might be more effective for labelling islets than [Ga]NODAGA-exendin-4. This is probably due to the lower specific radioactivity of [Ga]NODAGA-exendin-4 compared to [Cu]NODAGA-exendin-4. The radiation dose in the kidneys may limit the use of [Cu]NODAGA-exendin-4 as a clinical tracer. [ABSTRACT FROM AUTHOR]

Published
2014
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6. Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, 18F-labeled [Nle14,Lys40]exendin-4 analog, shows promise for clinical imaging

Author

Miikka Tarkia, Pirjo Nuutila, Tuula Tolvanen, Saila Kauhanen, Kirsi Mikkola, Olof Solin, Cheng-Bin Yim, Paula Lehtiniemi, Medicum, and Department of Pharmacology

Subjects
Biodistribution, Pathology, medicine.medical_specialty, endocrine system, TERMINAL ALKYNES, RADIONUCLIDE THERAPY, Pharmacology, Exendin, complex mixtures, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, fluids and secretions, In vivo, GLP-1 RECEPTOR, Medicine, Radiology, Nuclear Medicine and imaging, Pancreas, EXENDIN-4, HUMAN PANCREAS, medicine.diagnostic_test, business.industry, F-18, Pancreatic islets, digestive, oral, and skin physiology, RADIOLABELED PEPTIDES, PEPTIDE-1 RECEPTOR PET/CT, 3126 Surgery, anesthesiology, intensive care, radiology, beta cell, 3. Good health, INSULINOMA, PET, medicine.anatomical_structure, Positron emission tomography, 030220 oncology & carcinogenesis, Radionuclide therapy, Beta cell, RENAL UPTAKE, business, PRECLINICAL CHARACTERIZATION, Ex vivo, hormones, hormone substitutes, and hormone antagonists
Abstract

Background: Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for beta cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label beta cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. F-18-labeled [Nle(14), Lys(40)] exendin-4 analog ([F-18] exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [F-18] exendin-4 was assessed with ex vivo organ.-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of F-18 radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats. Results: [F-18] exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [F-18] exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin-based tracers, we observed rapid renal clearance of [F-18] exendin-4. Conclusions: [F-18] exendin-4 showed promise as a tracer for clinical imaging of pancreatic beta cells, due to its high specific uptake in native beta cells and its concomitant low kidney radioactivity uptake.

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