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Jaunsleine, K., Supe, L., Spura, J., van Beek, S., Sandström, A., Olsen, J., . . . Pelcman, B. (2024). Development of novel β2-adrenergic receptor agonists for the stimulation of glucose uptake – The importance of chirality and ring size of cyclic amines. Bioorganic & Medicinal Chemistry Letters, 97, Article ID 129562.
Open this publication in new window or tab >>Development of novel β2-adrenergic receptor agonists for the stimulation of glucose uptake – The importance of chirality and ring size of cyclic amines
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2024 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1464-3405, Vol. 97, article id 129562Article in journal (Refereed) Published
Abstract [en]

β2-Adrenergic receptor (β2AR) agonists have been reported to stimulate glucose uptake (GU) by skeletal muscle cells and are therefore highly interesting as a possible treatment for type 2 diabetes (T2D). The chirality of compounds often has a great impact on the activity of β2AR agonists, although this has thus far not been investigated for GU. Here we report the GU for a selection of synthesized acyclic and cyclic β-hydroxy-3-fluorophenethylamines. For the N-butyl and the N-(2-pentyl) compounds, the (R) and (R,R) (3d and 7e) stereoisomers induced the highest GU. When the compounds contained a saturated nitrogen containing 4- to 7-membered heterocycle, the (R,R,R) enantiomer of the azetidine (8a) and the pyrrolidine (9a) had the highest activity. Altogether, these results provide pivotal information for designing novel β2AR agonist for the treatment of T2D.

Keywords
β-Adrenergic receptor agonist, Cyclic amines, Diastereoselective synthesis, β-Hydroxy-phenethylamines, Muscle glucose uptake
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:su:diva-225751 (URN)10.1016/j.bmcl.2023.129562 (DOI)001125918700001 ()37967654 (PubMedID)2-s2.0-85178186966 (Scopus ID)
Available from: 2024-01-23 Created: 2024-01-23 Last updated: 2024-01-23Bibliographically approved
Ham, S., Mukaida, S., Sato, M., Keov, P., Bengtsson, T., Furness, S., . . . Hutchinson, D. S. (2024). Role of G protein-coupled receptor kinases (GRKs) in β2-adrenoceptor-mediated glucose uptake. Pharmacology Research & Perspectives, 12(1), Article ID e1176.
Open this publication in new window or tab >>Role of G protein-coupled receptor kinases (GRKs) in β2-adrenoceptor-mediated glucose uptake
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2024 (English)In: Pharmacology Research & Perspectives, E-ISSN 2052-1707, Vol. 12, no 1, article id e1176Article in journal (Refereed) Published
Abstract [en]

Truncation of the C-terminal tail of the beta(2)-AR, transfection of beta ARKct or over-expression of a kinase-dead GRK mutant reduces isoprenaline-stimulated glucose uptake, indicating that GRK is important for this response. We explored whether phosphorylation of the beta(2)-AR by GRK2 has a role in glucose uptake or if this response is related to the role of GRK2 as a scaffolding protein. CHO-GLUT4myc cells expressing wild-type and mutant beta(2)-ARs were generated and receptor affinity for [H-3]-CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344. Following receptor activation by beta(2)-AR agonists, cAMP accumulation, GLUT4 translocation, [H-3]-2-deoxyglucose uptake, and beta(2)-AR internalization were measured. Bioluminescence resonance energy transfer was used to investigate interactions between beta(2)-AR and beta-arrestin2 or between beta(2)-AR and GRK2. Glucose uptake after siRNA knockdown or GRK inhibitors was measured in response to beta(2)-AR agonists. BRL37344 was a poor partial agonist for cAMP generation but displayed similar potency and efficacy to isoprenaline for glucose uptake and GLUT4 translocation. These responses to beta(2)-AR agonists occurred in CHO-GLUT4myc cells expressing beta(2)-ARs lacking GRK or GRK/PKA phosphorylation sites as well as in cells expressing the wild-type beta(2)-AR. However, beta(2)-ARs lacking phosphorylation sites failed to recruit beta-arrestin2 and did not internalize. GRK2 knock-down or GRK2 inhibitors decreased isoprenaline-stimulated glucose uptake in rat L6 skeletal muscle cells. Thus, GRK phosphorylation of the beta(2)-AR is not associated with isoprenaline- or BRL37344-stimulated glucose uptake. However, GRKs acting as scaffold proteins are important for glucose uptake as GRK2 knock-down or GRK2 inhibition reduces isoprenaline-stimulated glucose uptake.

Keywords
glucose uptake, GRK2, beta(2) adrenoceptor
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-226949 (URN)10.1002/prp2.1176 (DOI)001159798500001 ()38332691 (PubMedID)
Available from: 2024-02-29 Created: 2024-02-29 Last updated: 2024-02-29Bibliographically approved
Iqbal, M. N., Jaworski, A., Pinon, A. C., Bengtsson, T. & Hedin, N. (2023). Activity and Stability of Nanoconfined Alpha-Amylase in Mesoporous Silica. ACS Materials Science Au, 3(6), 659-668
Open this publication in new window or tab >>Activity and Stability of Nanoconfined Alpha-Amylase in Mesoporous Silica
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2023 (English)In: ACS Materials Science Au, E-ISSN 2694-2461, Vol. 3, no 6, p. 659-668Article in journal (Refereed) Published
Abstract [en]

Mesoporous silica particles (MSPs) have been studied for their potential therapeutic uses in controlling obesity and diabetes. Previous studies have shown that the level of digestion of starch by α-amylase is considerably reduced in the presence of MSPs, and it has been shown to be caused by the adsorption of α-amylase by MSPs. In this study, we tested a hypothesis of enzymatic deactivation and measured the activity of α-amylase together with MSPs (SBA-15) using comparably small CNP-G3 (2-chloro-4-nitrophenyl alpha-d-maltotrioside) as a substrate. We showed that pore-incorporated α-amylase was active and displayed higher activity and stability compared to amylase in solution (the control). We attribute this to physical effects: the coadsorption of CNP-G3 on the MSPs and the relatively snug fit of the amylase in the pores. Biosorption in this article refers to the process of removal or adsorption of α-amylase from its solution phase into the same solution dispersed in, or adsorbed on, the MSPs. Large quantities of α-amylase were biosorbed (about 21% w/w) on the MSPs, and high values of the maximum reaction rate (Vmax) and the Michaelis–Menten constant (KM) were observed for the enzyme kinetics. These findings show that the reduced enzymatic activity for α-amylase on MSP observed here and in earlier studies was related to the large probe (starch) being too large to adsorb in the pores, and potato starch has indeed a hydrodynamic diameter much larger than the pore sizes of MSPs. Further insights into the interactions and environments of the α-amylase inside the MSPs were provided by 1H fast magic-angle spinning (MAS) nuclear magnetic resonance (NMR) and 13C/15N dynamic nuclear polarization MAS NMR experiments. It could be concluded that the overall fold and solvation of the α-amylase inside the MSPs were nearly identical to those in solution. 

Keywords
mesoporous silica particles, porcine pancreatic alpha-amylase, starch, 2-chloro-4-nitrophenyl alpha-d-maltotrioside (CNP-G3), (DNP) MAS NMR
National Category
Materials Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-214591 (URN)10.1021/acsmaterialsau.3c00028 (DOI)001042090400001 ()2-s2.0-85168508459 (Scopus ID)
Available from: 2023-02-06 Created: 2023-02-06 Last updated: 2024-01-11Bibliographically approved
van Beek, S. M. M., Bruls, Y. M. H., Vanweert, F., Fealy, C. E., Connell, N. J., Schaart, G., . . . Hoeks, J. (2023). Effect of β2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial. Nature Communications, 14, Article ID 173.
Open this publication in new window or tab >>Effect of β2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, article id 173Article in journal (Refereed) Published
Abstract [en]

β2-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents, likely via mTORC2-mediated signalling. However, human data on this topic is virtually absent. We here investigate the effects of two-weeks treatment with the β2-agonist clenbuterol (40 µg/day) on glucose control as well as energy- and substrate metabolism in healthy young men (age: 18-30 years, BMI: 20-25 kg/m2) in a randomised, placebo-controlled, double-blinded, cross-over study (ClinicalTrials.gov-identifier: NCT03800290). Randomisation occurred by controlled randomisation and the final allocation sequence was seven (period 1: clenbuterol, period 2: placebo) to four (period 1: placebo, period 2: clenbuterol). The primary and secondary outcome were peripheral insulin-stimulated glucose disposal and skeletal muscle GLUT4 translocation, respectively. Primary analyses were performed on eleven participants. No serious adverse events were reported. The study was performed at Maastricht University, Maastricht, The Netherlands, between August 2019 and April 2021. Clenbuterol treatment improved peripheral insulin-stimulated glucose disposal by 13% (46.6 ± 3.5 versus 41.2 ± 2.7 µmol/kg/min, p = 0.032), whereas skeletal muscle GLUT4 translocation assessed in overnight fasted muscle biopsies remained unaffected. These results highlight the potential of β2-agonist treatment in improving skeletal muscle glucose uptake and underscore the therapeutic value of this pathway for the treatment of type 2 diabetes. However, given the well-known (cardiovascular) side-effects of systemic β2-agonist treatment, further exploration on the underlying mechanisms is needed to identify viable therapeutic targets.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-217312 (URN)10.1038/s41467-023-35798-5 (DOI)000955726400008 ()36635304 (PubMedID)2-s2.0-85146194871 (Scopus ID)
Available from: 2023-05-24 Created: 2023-05-24 Last updated: 2023-05-24Bibliographically approved
Adori, M., Bhat, S., Gramignoli, R., Valladolid-Acebes, I., Bengtsson, T., Uhlèn, M. & Adori, C. (2023). Hepatic Innervations and Nonalcoholic Fatty Liver Disease. Seminars in liver disease (Print), 43(02), 149-162
Open this publication in new window or tab >>Hepatic Innervations and Nonalcoholic Fatty Liver Disease
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2023 (English)In: Seminars in liver disease (Print), ISSN 0272-8087, E-ISSN 1098-8971, Vol. 43, no 02, p. 149-162Article, review/survey (Refereed) Published
Abstract [en]

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Increased sympathetic (noradrenergic) nerve tone has a complex role in the etiopathomechanism of NAFLD, affecting the development/progression of steatosis, inflammation, fibrosis, and liver hemodynamical alterations. Also, lipid sensing by vagal afferent fibers is an important player in the development of hepatic steatosis. Moreover, disorganization and progressive degeneration of liver sympathetic nerves were recently described in human and experimental NAFLD. These structural alterations likely come along with impaired liver sympathetic nerve functionality and lack of adequate hepatic noradrenergic signaling. Here, we first overview the anatomy and physiology of liver nerves. Then, we discuss the nerve impairments in NAFLD and their pathophysiological consequences in hepatic metabolism, inflammation, fibrosis, and hemodynamics. We conclude that further studies considering the spatial-temporal dynamics of structural and functional changes in the hepatic nervous system may lead to more targeted pharmacotherapeutic advances in NAFLD.

Keywords
nonalcoholic fatty liver disease, sympathetic nerves, parasympathetic nerves, noradrenaline, steatosis, inflammation, fibrosis, portal hypertension
National Category
Cell and Molecular Biology Gastroenterology and Hepatology
Identifiers
urn:nbn:se:su:diva-220265 (URN)10.1055/s-0043-57237 (DOI)000983734600001 ()37156523 (PubMedID)2-s2.0-85164843176 (Scopus ID)
Available from: 2023-08-22 Created: 2023-08-22 Last updated: 2023-08-22Bibliographically approved
Iqbal, M. N., Robert-Nicoud, G., Ciurans-Oset, M., Akhtar, F., Hedin, N. & Bengtsson, T. (2023). Mesoporous Silica Particles Retain Their Structure and Function while Passing through the Gastrointestinal Tracts of Mice and Humans. ACS Applied Materials and Interfaces
Open this publication in new window or tab >>Mesoporous Silica Particles Retain Their Structure and Function while Passing through the Gastrointestinal Tracts of Mice and Humans
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2023 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, , p. 12Article in journal (Refereed) Published
Abstract [en]

Mesoporous silica particles (MSPs) can be used as food additives, clinically for therapeutic applications, or as oral delivery vehicles. It has also been discussed to be used for a number of novel applications including treatment for diabetes and obesity. However, a major question for their possible usage has been if these particles persist structurally and retain their effect when passing through the gastrointestinal tract (GIT). A substantial breaking down of the particles could reduce function and be clinically problematic for safety issues. Hence, we investigated the biostability of MSPs of the SBA-15 kind prepared at large scales (100 and 1000 L). The MSPs were orally administered in a murine model and clinically in humans. A joint extraction and calcination method was developed to recover the MSPs from fecal mass, and the MSPs were characterized physically, structurally, morphologically, and functionally before and after GIT passage. Analyses with N2 adsorption, X-ray diffraction, electron microscopy, and as a proxy for general function, adsorption of the enzyme α-amylase, were conducted. The adsorption capacity of α-amylase on extracted MSPs was not reduced as compared to the pristine and control MSPs, and adsorption of up to 17% (w/w) was measured. It was demonstrated that the particles did not break down to any substantial degree and retained their function after passing through the GITs of the murine model and in humans. The fact the particles were not absorbed into the body was ascribed to that they were micron-sized and ingested as agglomerates and too big to pass the intestinal barrier. The results strongly suggest that orally ingested MSPs can be used for a number of clinical applications. 

Publisher
p. 12
Keywords
mesoporous silica particles, biostability, gastrointestinal tract, protein adsorption, porcine pancreatic α-amylase
National Category
Materials Chemistry
Identifiers
urn:nbn:se:su:diva-214588 (URN)10.1021/acsami.2c16710 (DOI)000928638000001 ()2-s2.0-85147567459 (Scopus ID)
Available from: 2023-02-06 Created: 2023-02-06 Last updated: 2023-04-21Bibliographically approved
van Beek, S., Hashim, D., Bengtsson, T. & Hoeks, J. (2023). Physiological and molecular mechanisms of cold-induced improvements in glucose homeostasis in humans beyond brown adipose tissue. International Journal of Obesity, 47(5), 338-347
Open this publication in new window or tab >>Physiological and molecular mechanisms of cold-induced improvements in glucose homeostasis in humans beyond brown adipose tissue
2023 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 47, no 5, p. 338-347Article, review/survey (Refereed) Published
Abstract [en]

Exposure to low ambient temperatures has previously been demonstrated to markedly improve glucose homeostasis in both rodents and humans. Although the brown adipose tissue is key in mediating these beneficial effects in rodents, its contribution appears more limited in humans. Hence, the exact tissues and underlying mechanisms that mediate cold-induced improvements in glucose homeostasis in humans remain to be fully established. In this review, we evaluated the response of the main organs involved in glucose metabolism (i.e. pancreas, liver, (white) adipose tissue, and skeletal muscle) to cold exposure and discuss their potential contribution to cold-induced improvements in glucose homeostasis in humans. We here show that cold exposure has widespread effects on metabolic organs involved in glucose regulation. Nevertheless, cold-induced improvements in glucose homeostasis appear primarily mediated via adaptations within the skeletal muscle and (presumably) white adipose tissue. Since the underlying mechanisms remain elusive, future studies should be aimed at pinpointing the exact physiological and molecular mechanisms involved in humans. Nonetheless, cold exposure holds great promise as a novel, additive lifestyle approach to improve glucose homeostasis in insulin resistant individuals.

National Category
Physiology
Identifiers
urn:nbn:se:su:diva-215979 (URN)10.1038/s41366-023-01270-z (DOI)000937079800002 ()36774412 (PubMedID)2-s2.0-85147767948 (Scopus ID)
Available from: 2023-04-14 Created: 2023-04-14 Last updated: 2023-05-12Bibliographically approved
Giannisis, A., Patra, K., Edlund, A. K., Nieto, L. A., Benedicto-Gras, J., Moussaud, S., . . . Nielsen, H. M. (2022). Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice. Molecular Psychiatry, 27(8), 3533-3543
Open this publication in new window or tab >>Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice
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2022 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 8, p. 3533-3543Article in journal (Refereed) Published
Abstract [en]

Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer’s disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah−/−, Rag2−/−, Il2rg−/− mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk of neurodegenerative disease.

National Category
Neurosciences
Identifiers
urn:nbn:se:su:diva-204349 (URN)10.1038/s41380-022-01548-0 (DOI)000783462300001 ()35418601 (PubMedID)2-s2.0-85128029153 (Scopus ID)
Available from: 2022-05-09 Created: 2022-05-09 Last updated: 2023-04-21Bibliographically approved
Gómez Rodríguez, A., Talamonti, E., Naudi, A., Kalinovich, A. V., Pauter, A. M., Barja, G., . . . Shabalina, I. G. (2022). Elovl2-Ablation Leads to Mitochondrial Membrane Fatty Acid Remodeling and Reduced Efficiency in Mouse Liver Mitochondria. Nutrients, 14(3), Article ID 559.
Open this publication in new window or tab >>Elovl2-Ablation Leads to Mitochondrial Membrane Fatty Acid Remodeling and Reduced Efficiency in Mouse Liver Mitochondria
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2022 (English)In: Nutrients, E-ISSN 2072-6643, Vol. 14, no 3, article id 559Article in journal (Refereed) Published
Abstract [en]

The fatty acid elongase elongation of very long-chain fatty acids protein 2 (ELOVL2) controls the elongation of polyunsaturated fatty acids (PUFA) producing precursors for omega-3, docosahexaenoic acid (DHA), and omega-6, docosapentaenoic acid (DPAn-6) in vivo. Expectedly, Elovl2-ablation drastically reduced the DHA and DPAn-6 in liver mitochondrial membranes. Unexpectedly, however, total PUFAs levels decreased further than could be explained by Elovl2 ablation. The lipid peroxidation process was not involved in PUFAs reduction since malondialdehyde-lysine (MDAL) and other oxidative stress biomarkers were not enhanced. The content of mitochondrial respiratory chain proteins remained unchanged. Still, membrane remodeling was associated with the high voltage-dependent anion channel (VDAC) and adenine nucleotide translocase 2 (ANT2), a possible reflection of the increased demand on phospholipid transport to the mitochondria. Mitochondrial function was impaired despite preserved content of the respiratory chain proteins and the absence of oxidative damage. Oligomycin-insensitive oxygen consumption increased, and coefficients of respiratory control were reduced by 50%. The mitochondria became very sensitive to fatty acid-induced uncoupling and permeabilization, where ANT2 is involved. Mitochondrial volume and number of peroxisomes increased as revealed by transmission electron microscopy. In conclusion, the results imply that endogenous DHA production is vital for the normal function of mouse liver mitochondria and could be relevant not only for mice but also for human metabolism.

Keywords
docosahexaenoic acid (DHA) deficiency, mitochondrial function, polyunsaturated fatty acids, membrane permeabilization, oxidative damage markers, adenine nucleotide translocase
National Category
Health Sciences
Identifiers
urn:nbn:se:su:diva-202398 (URN)10.3390/nu14030559 (DOI)000754768000001 ()
Available from: 2022-02-24 Created: 2022-02-24 Last updated: 2023-08-28Bibliographically approved
Baek, J., Robert-Nicoud, G., Herrera Hidalgo, C., Borg, M. L., Iqbal, M. N., Berlin, R., . . . Bengtsson, T. (2022). Engineered mesoporous silica reduces long-term blood glucose and HbA1c, and improves metabolic parameters in prediabetics. Nanomedicine, 17(1), 9-22
Open this publication in new window or tab >>Engineered mesoporous silica reduces long-term blood glucose and HbA1c, and improves metabolic parameters in prediabetics
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2022 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 17, no 1, p. 9-22Article in journal (Refereed) Published
Abstract [en]

Aim: To investigate the effect of oral consumption of engineered mesoporous silica particles, SiPore15®, on long-term blood glucose levels and other metabolic parameters in individuals with prediabetes and newly diagnosed Type 2 diabetes. Method: An open-label, single-arm, multicenter trial was conducted in which SiPore15 was consumed three times daily for 12 weeks. Hemoglobin A1c (HbA1c, primary end point) and an array of metabolic parameters were measured at baseline and throughout the trial. Result: SiPore15 treatment significantly reduced HbA1c by a clinically meaningful degree and improved several disease-associated parameters with minimal side effects. Conclusion: The results from this study demonstrate the potential use of SiPore15 as a treatment for prediabetes that may also delay or prevent the onset of Type 2 diabetes.

Keywords
diabetes prevention, HbA1c, medical device, mesoporous silica particles, prediabetes, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-201430 (URN)10.2217/nnm-2021-0235 (DOI)000725078400001 ()
Available from: 2022-02-01 Created: 2022-02-01 Last updated: 2022-02-01Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5396-030x

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