1. |
- Drott, Carl Johan, 1984-, et al.
(author)
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CART decreases islet blood flow, but has no effect on total pancreatic blood flow and glucose tolerance in anesthetized rats
- 2021
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In: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 135
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Journal article (peer-reviewed)abstract
- Cocaine- and amphetamine-regulated transcript (CART) is a neurotransmitter and hormone, involved in the regulation of e.g. food intake, body weight, reward and addiction, and stress response. CART has also been found to affect insulin secretion and beta cell morphology, both in vivo and in vitro. Furthermore, CART affects regulation of the cardiovascular system and helps to modulate vascular tone. The present study evaluated the local effect of CART on the pancreatic and islet circulation and function. CART (25 µg/h) or saline, combinations of CART and endothelin-A receptor antagonist (BQ123; 100 µg/kg), and glucose (2 g/kg) were intravenously infused in Sprague Dawley rats followed by blood flow measurements using a microsphere technique. Separately, CART-infused animals underwent an intravenous glucose tolerance test (ivGTT). The direct effect of CART on insulin release was investigated using isolated islets from Sprague Dawley rats. CART reduced islet blood flow, without reduction in total pancreatic blood flow. The normal glucose-induced islet blood flow increase was diminished by CART, albeit still present. Simultaneously, CART had no effect on systemic-, intestinal- or renal blood flow. The endothelin-A receptor antagonist BQ123 together with CART had no pancreatic vascular effects. We found that CART has pronounced vascular constrictive actions restricted to the pancreatic islet circulation but had no effect on insulin release neither in vivo nor in vitro. The mechanisms behind the vascular effects are still unknown, but may reflect a direct action on pancreatic blood vessels.
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2. |
- Drott, Carl Johan, 1984-, et al.
(author)
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Irisin is present in α cells and decreases islet blood flow
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Other publication (other academic/artistic)abstract
- Irisin is a myokine involved in glucose homeostasis, and is primarily expressed in skeletal muscle and adipose tissue but also in multiple tissues, among them, the pancreas. We aimed to elucidate the cell-specific expression and secretion of irisin, as well as the effect of irisin, in the pancreas. Irisin was observed to be expressed predominantly in α cells, and perifusion of human islets with glucose demonstrated that irisin was secreted in a glucose-dependent manner. Intravenous infusion of irisin in Sprague-Dawley rats resulted in a nearly 50% reduction of islet blood flow compared to control. However, neither irisin nor an irisin neutralizing antibody affected insulin secretion from rat or human islets in vitro. We conclude that irisin has a novel role in pancreatic islet physiology, being secreted by α cells in response to glucose, i.e. in an inverse manner to glucagon, and exerting local vascular effects diminishing islet blood flow while not affecting insulin secretion per se.
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3. |
- Norman, Daniel, et al.
(author)
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Irisin-A Pancreatic Islet Hormone
- 2022
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In: Biomedicines. - : MDPI. - 2227-9059. ; 10:2
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Journal article (peer-reviewed)abstract
- Irisin is a myokine involved in glucose homeostasis. It is primarily expressed in skeletal muscle, but also in the pancreas. This study aimed to elucidate its presence and role in the islets of Langerhans-i.e., its effect on insulin and glucagon secretion as well as on blood flow in the pancreas. The precursor of irisin, fibronectin type III domain-containing protein 5 (FNDC5), was identified in rat and human islets by both qPCR and immunohistochemistry. Both alpha- and beta-cells stained positive for FNDC5. In human islets, we found that irisin was secreted in a glucose-dependent manner. Neither irisin nor an irisin-neutralizing antibody affected insulin or glucagon secretion from human or rat islets in vitro. The insulin and glucagon content in islets was not altered by irisin. The intravenous infusion of irisin in Sprague Dawley rats resulted in nearly 50% reduction in islet blood flow compared to the control. We conclude that irisin is an islet hormone that has a novel role in pancreatic islet physiology, exerting local vascular effects by diminishing islet blood flow without affecting insulin secretion per se.
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4. |
- Norman, Daniel, 1997-
(author)
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Physiological Studies of Native and Stem Cell-Derived Islets
- 2024
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Doctoral thesis (other academic/artistic)abstract
- In type 1 and type 2 diabetes, the β-cells of the islets of Langerhans are either destroyed by the immune system or stressed due to peripheral insulin resistance. To improve the life of patients with these diseases, new treatments are needed. This thesis examined the role of irisin and cocaine and amphetamine regulated transcript (CART) in islets of Langerhans and their potential pharmaceutical role in type 2 diabetes. Furthermore, β-cell replacement with stem cell-derived islets of Langerhans (SC-islets) for type 1 diabetes was evaluated for optimal implantation site.In paper I, the physiological role of CART in rat islets was examined. CART was shown to specifically lower islet blood flow, which could be a protective effect in type 2 diabetes. No effect from CART on glucose tolerance or insulin release was seen in rat islets, which highlights species differences.In paper II, the expression of irisin and its effect on hormone secretion and pancreatic blood flow was examined. Irisin was expressed in human islets and was secreted glucose dependently. It also lowered islet blood flow but did not affect glucose-stimulated insulin secretion in isolated human or rat islets. Thus, local secretion of irisin could serve as a protective function by lowering islet blood flow in a high glucose state.In paper III, the expression of irisin in SC-islets and its potential beneficial effects in transplantation was examined. SC-islets were found to express higher levels of irisin than human islets. Irisin treatment had no effects on viability and proliferation in SC-islets, in contrast to previous studies in other species. Thus, irisin signaling likely differs between SC-islets and murine and native human islets.In paper IV, SC-islets were transplanted to multiple sites in mice to find the optimal implantation site in terms of graft maturity, function and composition. The liver proved to be the most favorable site due to its higher expression of islet maturity genes and a higher β-cell function and fraction. This poses a dilemma, as the liver site is the most challenging to biopsy and monitor for safety.In summary, this thesis uncovered new physiological functions of irisin and CART, potentially offering insights relevant to the treatment of type 2 diabetes. Meanwhile, the role of irisin in transplantation of SC-islets seems limited.
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5. |
- Bhandage, Amol, 1988-, et al.
(author)
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Expression of calcium release-activated and voltage-gated calcium channels genes in peripheral blood mononuclear cells is altered in pregnancy and in type 1 diabetes
- 2018
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
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Journal article (peer-reviewed)abstract
- Calcium (Ca2+) is an important ion in physiology and is found both outside and inside cells. The intracellular concentration of Ca2+ is tightly regulated as it is an intracellular signal molecule and can affect a variety of cellular processes. In immune cells Ca2+ has been shown to regulate e.g. gene transcription, cytokine secretion, proliferation and migration. Ca2+ can enter the cytoplasm either from intracellular stores or from outside the cells when Ca2+ permeable ion channels in the plasma membrane open. The Ca2+ release-activated (CRAC) channel is the most prominent Ca2+ ion channel in the plasma membrane. It is formed by ORAI1-3 and the channel is opened by the endoplasmic reticulum Ca2+ sensor proteins stromal interaction molecules (STIM) 1 and 2. Another group of Ca-2(+) channels in the plasma membrane are the voltage-gated Ca2+ (Ca-V) channels. We examined if a change in immunological tolerance is accompanied by altered ORAI, STIM and Ca-V gene expression in peripheral blood mononuclear cells (PBMCs) in pregnant women and in type 1 diabetic individuals. Our results show that in pregnancy and type 1 diabetes ORAI1-3 are up-regulated whereas STIM1 and 2 are down-regulated in pregnancy but only STIM2 in type 1 diabetes. Expression of L-, P/Q-, R- and T-type voltage-gated Ca2+ channels was detected in the PBMCs where the Ca(V)2.3 gene was up-regulated in pregnancy and type 1 diabetes whereas the Ca(V)2.1 and Ca(V)3.2 genes were up-regulated only in pregnancy and the Ca(V)1.3 gene in type 1 diabetes. The results are consistent with that expression of ORAI, STIM and Ca-V genes correlate with a shift in immunological status of the individual in health, as during pregnancy, and in the autoimmune disease type 1 diabetes. Whether the changes are in general protective or in type 1 diabetes include some pathogenic components remains to be clarified.
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6. |
- Bhandage, Amol K., 1988-, et al.
(author)
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GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes
- 2018
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In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 30, s. 283-294
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Journal article (peer-reviewed)abstract
- The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.
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7. |
- Brandao, Luiz Eduardo M., et al.
(author)
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Acute sleep loss alters circulating fibroblast growth factor 21 levels in humans: A randomised crossover trial
- 2022
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In: Journal of Sleep Research. - : Wiley. - 0962-1105 .- 1365-2869. ; 31:2
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Journal article (peer-reviewed)abstract
- The hormone fibroblast growth factor 21 (FGF21) modulates tissue metabolism and circulates at higher levels in metabolic conditions associated with chronic sleep-wake disruption, such as type 2 diabetes and obesity. In the present study, we investigated whether acute sleep loss impacts circulating levels of FGF21 and tissue-specific production, and response pathways linked to FGF21. A total of 15 healthy normal-weight young men participated in a randomised crossover study with two conditions, sleep loss versus an 8.5-hr sleep window. The evening before each intervention, fasting blood was collected. Fasting, post-intervention morning skeletal muscle and adipose tissue samples underwent quantitative polymerase chain reaction and DNA methylation analyses, and serum FGF21 levels were measured before and after an oral glucose tolerance test. Serum levels of FGF21 were higher after sleep loss compared with sleep, both under fasting conditions and following glucose intake (similar to 27%-30%, p = 0.023). Fasting circulating levels of fibroblast activation protein, a protein which can degrade circulating FGF21, were not altered by sleep loss, whereas DNA methylation in the FGF21 promoter region increased only in adipose tissue. However, even though specifically the muscle exhibited transcriptional changes indicating adverse alterations to redox and metabolic homeostasis, no tissue-based changes were observed in expression of FGF21, its receptors, or selected signalling targets, in response to sleep loss. In summary, we found that acute sleep loss resulted in increased circulating levels of FGF21 in healthy young men, which may occur independent of a tissue-based stress response in metabolic peripheral tissues. Further studies may decipher whether changes in FGF21 signalling after sleep loss modulate metabolic outcomes associated with sleep or circadian disruption.
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8. |
- Brboric, Anja, et al.
(author)
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Characterization of neural crest-derived stem cells isolated from human bone marrow for improvement of transplanted islet function.
- 2019
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In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 124:4, s. 228-237
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Journal article (peer-reviewed)abstract
- Background: Murine boundary cap-derived neural crest stem cells (NCSCs) are capable of enhancing islet function by stimulating beta cell proliferation as well as increasing the neural and vascular density in the islets both in vitro and in vivo. This study aimed to isolate NCSC-like cells from human bone marrow.Methods: CD271 magnetic cell separation and culture techniques were used to purify a NCSC-enriched population of human bone marrow. Analyses of the CD271+ and CD271- fractions in terms of protein expression were performed, and the capacity of the CD271+ bone marrow cells to form 3-dimensional spheres when grown under non-adherent conditions was also investigated. Moreover, the NCSC characteristics of the CD271+ cells were evaluated by their ability to migrate toward human islets as well as human islet-like cell clusters (ICC) derived from pluripotent stem cells.Results: The CD271+ bone marrow population fulfilled the criterion of being multipotent stem cells, having the potential to differentiate into glial cells, neurons as well as myofibroblasts in vitro. They had the capacity to form 3-dimensional spheres as well as an ability to migrate toward human islets, further supporting their NCSC identity. Additionally, we demonstrated similar migration features toward stem cell-derived ICC.Conclusion: The results support the NCSC identity of the CD271-enriched human bone marrow population. It remains to investigate whether the human bone marrow-derived NCSCs have the ability to improve transplantation efficacy of not only human islets but stem cell-derived ICC as well.
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9. |
- Carlbom, Lina, et al.
(author)
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[(11)C]5-Hydroxy-Tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes
- 2017
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:5, s. 1286-1292
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Journal article (peer-reviewed)abstract
- [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP) PET of the pancreas has been shown to be a surrogate imaging biomarker of pancreatic islet mass. The change in islet mass in different stages of type 2 diabetes (T2D) as measured by non-invasive imaging is currently unknown. Here, we describe a cross-sectional study where subjects at different stages of T2D development with expected stratification of pancreatic islet mass were examined in relation to non-diabetic individuals. The primary outcome was the [(11)C]5-HTP uptake and retention in pancreas, as a surrogate marker for the endogenous islet mass.We found that metabolic testing indicated a progressive loss of beta cell function, but that this was not mirrored by a decrease in [(11)C]5-HTP tracer accumulation in the pancreas. This provides evidence of retained islet mass despite decreased beta cell function. The results herein indicates that beta cell dedifferentiation, and not necessarily endocrine cell loss, constitute a major cause of beta cell failure in T2D.
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10. |
- Carlbom, Lina, et al.
(author)
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Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes
- 2016
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:9, s. 1968-1972
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: The aim of this study was to investigate pancreatic perfusion and its response to a glucose load in patients with type 1 diabetes mellitus compared with non-diabetic ('healthy') individuals.METHODS: Eight individuals with longstanding type 1 diabetes and ten sex-, age- and BMI-matched healthy controls underwent dynamic positron emission tomography scanning with (15)O-labelled water before and after intravenous administration of glucose. Perfusion in the pancreas was measured. Portal and arterial hepatic perfusion were recorded as references.RESULTS: Under fasting conditions, total pancreatic perfusion was on average 23% lower in the individuals with diabetes compared with healthy individuals. Glucose increased total pancreatic and portal hepatic blood perfusion in healthy individuals by 48% and 38%, respectively. In individuals with diabetes there was no significant increase in either total pancreatic or portal hepatic perfusion.CONCLUSIONS/INTERPRETATION: Individuals with type 1 diabetes have reduced basal pancreatic perfusion and a severely impaired pancreatic and splanchnic perfusion response to intravenous glucose stimulation.
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11. |
- Carlsson, Per-Ola, et al.
(author)
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Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus
- 2018
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In: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 18:7, s. 1735-1744
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Journal article (peer-reviewed)abstract
- 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.
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12. |
- Carlsson, Per-Ola, et al.
(author)
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Umbilical cord-derived mesenchymal stromal cells preserve endogenous insulin production in type 1 diabetes : a Phase I/II randomised double-blind placebo-controlled trial
- 2023
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In: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 66:8, s. 1431-1441
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Journal article (peer-reviewed)abstract
- Aim/hypothesis This study aimed to investigate the safety and efficacy of treatment with allogeneic Wharton's jelly-derived mesenchymal stromal cells (MSCs) in recent-onset type 1 diabetes.Methods A combined Phase I/II trial, composed of a dose escalation followed by a randomised double-blind placebo-controlled study in parallel design, was performed in which treatment with allogeneic MSCs produced as an advanced therapy medicinal product (ProTrans) was compared with placebo in adults with newly diagnosed type 1 diabetes. Inclusion criteria were a diagnosis of type 1 diabetes <2 years before enrolment, age 18-40 years and a fasting plasma C-peptide concentration >0.12 nmol/l. Randomisation was performed with a web-based randomisation system, with a randomisation code created prior to the start of the study. The randomisation was made in blocks, with participants randomised to ProTrans or placebo treatment. Randomisation envelopes were kept at the clinic in a locked room, with study staff opening the envelopes at the baseline visits. All participants and study personnel were blinded to group assignment. The study was conducted at Karolinska University Hospital, Stockholm, Sweden.Results Three participants were included in each dose cohort during the first part of the study. Fifteen participants were randomised in the second part of the study, with ten participants assigned to ProTrans treatment and five to placebo. All participants were analysed for the primary and secondary outcomes. No serious adverse events related to treatment were observed and, overall, few adverse events (mainly mild upper respiratory tract infections) were reported in the active treatment and placebo arms. The primary efficacy endpoint was defined as Delta-change in C-peptide AUC for a mixed meal tolerance test at 1 year following ProTrans/placebo infusion compared with baseline performance prior to treatment. C-peptide levels in placebo-treated individuals declined by 47%, whereas those in ProTrans-treated individuals declined by only 10% (p<0.05). Similarly, insulin requirements increased in placebo-treated individuals by a median of 10 U/day, whereas insulin needs of ProTrans-treated individuals did not change over the follow-up period of 12 months (p<0.05).Conclusions/interpretation This study suggests that allogeneic Wharton's jelly-derived MSCs (ProTrans) is a safe treatment for recent-onset type 1 diabetes, with the potential to preserve beta cell function.
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13. |
- Cederblad, Lars, et al.
(author)
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Classification of Hypoglycemic Events in Type 1 Diabetes Using Machine Learning Algorithms
- 2023
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In: Diabetes Therapy. - : Springer Nature. - 1869-6953 .- 1869-6961. ; 14:6, s. 953-965
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Journal article (peer-reviewed)abstract
- IntroductionTo improve the utilization of continuous- and flash glucose monitoring (CGM/FGM) data we have tested the hypothesis that a machine learning (ML) model can be trained to identify the most likely root causes for hypoglycemic events.MethodsCGM/FGM data were collected from 449 patients with type 1 diabetes. Of the 42,120 identified hypoglycemic events, 5041 were randomly selected for classification by two clinicians. Three causes of hypoglycemia were deemed possible to interpret and later validate by insulin and carbohydrate recordings: (1) overestimated bolus (27%), (2) overcorrection of hyperglycemia (29%) and (3) excessive basal insulin presure (44%). The dataset was split into a training (n = 4026 events, 304 patients) and an internal validation dataset (n = 1015 events, 145 patients). A number of ML model architectures were applied and evaluated. A separate dataset was generated from 22 patients (13 ‘known’ and 9 ‘unknown’) with insulin and carbohydrate recordings. Hypoglycemic events from this dataset were also interpreted by five clinicians independently.ResultsOf the evaluated ML models, a purpose-built convolutional neural network (HypoCNN) performed best. Masking the time series, adding time features and using class weights improved the performance of this model, resulting in an average area under the curve (AUC) of 0.921 in the original train/test split. In the dataset validated by insulin and carbohydrate recordings (n = 435 events), i.e. ‘ground truth,’ our HypoCNN model achieved an AUC of 0.917.ConclusionsThe findings support the notion that ML models can be trained to interpret CGM/FGM data. Our HypoCNN model provides a robust and accurate method to identify root causes of hypoglycemic events.
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14. |
- Elksnis, Andris, et al.
(author)
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Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass
- 2019
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In: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 10
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Research review (peer-reviewed)abstract
- Type 2 diabetes (T2D) is a complex and heterogeneous disease which affects millions of people worldwide. The classification of diabetes is at an interesting turning point and there have been several recent reports on sub-classification of T2D based on phenotypical and metabolic characteristics. An important, and perhaps so far underestimated, factor in the pathophysiology of T2D is the role of oxidative stress and reactive oxygen species (ROS). There are multiple pathways for excessive ROS formation in T2D and in addition, beta-cells have an inherent deficit in the capacity to cope with oxidative stress. ROS formation could be causal, but also contribute to a large number of the metabolic defects in T2D, including beta-cell dysfunction and loss. Currently, our knowledge on beta-cell mass is limited to autopsy studies and based on comparisons with healthy controls. The combined evidence suggests that beta-cell mass is unaltered at onset of T2D but that it declines progressively. In order to better understand the pathophysiology of T2D, to identify and evaluate novel treatments, there is a need for in vivo techniques able to quantify beta-cell mass. Positron emission tomography holds great potential for this purpose and can in addition map metabolic defects, including ROS activity, in specific tissue compartments. In this review, we highlight the different phenotypical features of T2D and how metabolic defects impact oxidative stress and ROS formation. In addition, we review the literature on alterations of beta-cell mass in T2D and discuss potential techniques to assess beta-cell mass and metabolic defects in vivo.
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15. |
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16. |
- Eriksson, Olof, et al.
(author)
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Metabolically Active Brown Adipose Tissue Is Found in Adult Subjects with Type 1 Diabetes.
- 2019
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 20:23
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Journal article (peer-reviewed)abstract
- Type 1 diabetes (T1D) is characterized by the loss of insulin-producing cells and hence insulin secretion and metabolic control. In addition to insulin, there are a number of hormones and cytokines that influence metabolism, and many of these can be secreted from brown adipose tissue (BAT). However, the presence and activity of BAT in T1D have not been studied, despite the fact that preclinical studies have shown that transplantation of BAT in mouse models of T1D can restore metabolic control. The metabolic activity of BAT, white adipose tissue (WAT), and skeletal muscle was investigated in patients with T1D (n = 11) by 2-deoxy-2-(18F)fluoro-D-glucose PET/CT after cold stimulation. Functional BAT was detected in 4 out of 11 individuals with T1D with a prevalence of 36%. The glucose utilization rate in the supraclavicular BAT regions ranged from 0.75-38.7 µmol × min-1 × 100 g-1. The glucose utilization per gram tissue was higher in BAT when compared with both WAT (p = 0.049) and skeletal muscle (p = 0.039). However, no correlation between BAT activity and metabolic control or insulin requirements was found. In conclusion, for the first time, cold-induced BAT was detected in patients with T1D with a wide range in metabolic activity. Contrary to findings in animal models, the metabolic activity of BAT had negligible impact on insulin requirements or metabolic control in T1D under normal physiological conditions.
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17. |
- Eriksson, Olof, et al.
(author)
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The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue
- 2015
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 56:12, s. 1937-1941
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Journal article (peer-reviewed)abstract
- Recently, the existence of significant deposits of brown adipose tissue (BAT) in human adults was confirmed. Its role in the human metabolism is unknown but could be substantial. Inhibition of the cannabinoid receptor-1 (CB1) by the antagonist rimonabant (SR141716) has been associated with activation of BAT thermogenesis and weight loss in mice and rats. The role of peripheral and central CB1 in the activation of BAT merits further investigation. Here we developed a technique for quantifying CB1 in BAT by PET. Methods: Sections of rat BAT and subcutaneous white adipose tissue (WAT) were stained for CB1 and uncoupling protein-1 by immunofluorescent staining. Binding of the radiolabeled CB1 antagonist (3R,5R)-5-(3-(18F-fluoromethoxy)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)-phenyl)pyrrolidin-2-one (F-18-FMPEP-d(2)) to BAT in vivo and in vitro was assessed in rats by PET. Results: We found that CB1 was colocalized with uncoupling protein-1 in BAT, but neither protein was found in WAT. Binding of the radiotracer to BAT sections (but not WAT) in vitro was high and displaceable by pretreatment with rimonabant. Deposits of BAT in rats had significant binding of F-18-FMPEP-d(2) in vivo, indicating high CB1 density. WAT deposits were negative for F-18-FMPEP-d(2), consistent with the immunofluorescent staining and in vitro results. Conclusion: F-18-FMPEP-d(2) PET can quantify CB1 density noninvasively in vivo in rats. CB1 is therefore a promising surrogate imaging biomarker for assessing the presence of BAT deposits as well as for elucidating the mechanism of CB1 antagonist-mediated weight loss.
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18. |
- Eriksson, Olof, et al.
(author)
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The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas
- 2014
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:10, s. 3428-3437
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Journal article (peer-reviewed)abstract
- In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.
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19. |
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20. |
- Espes, Daniel, et al.
(author)
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Betatrophin in Diabetes Mellitus : the Epidemiological Evidence in Humans
- 2015
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In: Current Diabetes Reports. - : Springer Science and Business Media LLC. - 1534-4827 .- 1539-0829. ; 15:12
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Research review (peer-reviewed)abstract
- The prevalence of type 2 diabetes is increasing worldwide, and while numerous treatments exist, none of the current pharmacologic therapies is curative. Pharmacologic approaches that increase beta cell mass may present an avenue for actual cure. There have been numerous reports on factors that can induce beta cell proliferation in rodents, whereas there are still very limited data on the occurrence of beta cell proliferation in humans. The recent discovery of the hormone betatrophin, which in mice counteracted glucose intolerance induced by insulin resistance by potently stimulating beta cell proliferation, has boosted the hope for a new target for drug development for the treatment of diabetes mellitus in humans. With the encouraging preclinical findings as a background, this review presents the available clinical data on betatrophin and discusses its possible role in humans.
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21. |
- Espes, Daniel, et al.
(author)
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Cotransplantation of Polymerized Hemoglobin Reduces β-Cell Hypoxia and Improves β-Cell Function in Intramuscular Islet Grafts
- 2015
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 99:10, s. 2077-2082
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Journal article (peer-reviewed)abstract
- Background. Muscle is a promising alternative site for islet transplantation that facilitates rapid restoration of islet vascularization. However, the development of fibrosis suggests massive cellular death after transplantation. This study tested the hypothesis that islet graft function is limited by hypoxia-related death early after intramuscular transplantation, but that this can be overcome by cotransplantation of an oxygen carrier, that is, polymerized bovine hemoglobin (PolyHb). Methods. Two hundred islets were transplanted with or without different doses of PolyHb intramuscularly to nondiabetic C57BL/6 and diabetic C57BL/6 nu/nu mice. beta-cell hypoxia and apoptosis were evaluated by immunohistochemistry after injection of the biochemical marker pimonidazole or by staining for caspase-3, respectively. Blood glucose concentrations were monitored for 30 days after islet transplantation and animals were then subjected to an intravenous glucose tolerance test. Results. Substantial hypoxia was observed in control islet grafts during the first 4 days after transplantation. Cotransplantation of PolyHb resulted in a dose-dependent reduction of beta-cell hypoxia, but beta-cell apoptosis was only reduced by cotransplantation of low-dose PolyHb (0.03 mg/g body weight) due to the inflammatory effects of higher PolyHb concentrations. Cotransplantation of low-dose PolyHb resulted in improved islet graft function 30 days after transplantation in diabetic mice, with a glucose tolerance comparable to transplantation of 50% more islets. Conclusion. We conclude that cotransplantation of islets with PolyHb can be used to effectively bridge the critical hypoxic phase immediately after transplantation, improve islet graft function, and reduce the number of islets needed for successful intramuscular transplantation.
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22. |
- Espes, Daniel, 1985-
(author)
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Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Islet transplantation is a possible curative treatment for type 1 diabetes (T1D). Currently the liver dominates as implantation site, despite the many challenges encountered at this site.Acute hypoxia in islets transplanted to muscle and omentum, two possible alternative sites, was prevailing. However, it was rapidly reversed at both implantation sites, in contrast to when islets were transplanted intraportally. At the intramuscular site hypoxia was further relieved by co-transplantation of an oxygen carrier, polymerized hemoglobin, which also improved the functional outcome. The complement system was activated after islet transplantation to muscle, but did not hamper graft function.Both mouse and human islets transplanted to omentum become well re-vascularized and have a functional blood flow and oxygenation comparable with that of endogenous islets. Animals transplanted with islets to the omentum had a superior graft function compared with animals receiving intraportal islet grafts.Alloxan-diabetic animals were cured with a low number of islets both when the islets were implanted in the omentum and muscle. The islet grafts responded adequately to both glucose and insulin and displayed a favorable mRNA gene expression profile.A challenge in diabetes research and in islet transplantation is that there are no established techniques for quantifying beta-cell mass in vivo. By using radiolabeled Exendin-4, a GLP-1 receptor agonist, beta-cell mass after transplantation to muscle of mice was quantified. The results may well be translated to the clinical setting.By comparing the pancreatic accumulation of [11C]5-hydroxy tryptophan ([11C]5-HTP) as detected by positron emission tomography (PET) in T1D patients with that of healthy controls, a 66% decrease was observed. This may in fact represent the loss of beta-cells, taking into account that other cells within the islets of Langerhans are largely unaffected in T1D. In conclusion, the data presented support the use of alternative implantation sites for islet transplantation. In addition to improving the functional outcome this may enable more transplantations since the number of transplanted islets may be reduced. The techniques investigated for quantifying transplanted and endogenous beta-cell mass may greatly improve our knowledge of the pathophysiology of T1D and become a valuable tool for evaluation of beta-cell mass.
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23. |
- Espes, Daniel, 1985-, et al.
(author)
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Function and Gene Expression of Islets Experimentally Transplanted to Muscle and Omentum
- 2020
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In: Cell Transplantation. - THOUSAND OAKS, CA USA : SAGE Publications. - 0963-6897 .- 1555-3892. ; 29, s. 1-10
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Journal article (peer-reviewed)abstract
- Islet transplantation to the liver is a potential curative treatment for patients with type 1 diabetes. Muscle and the greater omentum are two alternative implantation sites, which can provide excellent engraftment and hold potential as future sites for stem-cell-derived beta-cell replacement. We evaluated the functional outcome after islet transplantation to muscle and omentum and found that alloxan-diabetic animals were cured with a low number of islets (200) at both sites. The cured animals had a normal area under the curve blood glucose response to intravenous glucose, albeit animals with intramuscular islet grafts had increased 120-min blood glucose levels. They also demonstrated an exaggerated counter regulatory response to hypoglycemia. The expression of genes important for beta-cell function was, at both implantation sites, comparable to that in native pancreatic islets. The gene expression of insulin (INS1 and INS2) and glucose transporter-2 was even increased, and the expression of lactate dehydrogenase decreased, at both sites when compared to native islets. We conclude that muscle and omentum provide excellent conditions for engraftment of transplanted islets. When compared to control, 200 islets implanted to the omentum displayed a restored glucose tolerance, whereas animals with intramuscular islet grafts of similar size displayed mild glucose intolerance.
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24. |
- Espes, Daniel, 1985-, et al.
(author)
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GABA induces a hormonal counter-regulatory response in subjects with long-standing type 1 diabetes
- 2021
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In: BMJ Open Diabetes Research & Care. - : BMJ Publishing Group Ltd. - 2052-4897. ; 9
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Journal article (peer-reviewed)abstract
- Introduction: Experimentally, gamma-aminobutyric acid (GABA) has been found to exert immune-modulatory effects and induce beta-cell regeneration, which make it a highly interesting substance candidate for the treatment of type 1 diabetes (T1D). In many countries, including those in the European Union, GABA is considered a pharmaceutical drug. We have therefore conducted a safety and dose escalation trial with the first controlled-release formulation of GABA, Remygen (Diamyd Medical).Research design and methods: Six adult male subjects with long-standing T1D (age 24.8 +/- 1.5 years, disease duration 14.7 +/- 2.2 years) were enrolled in an 11-day dose escalation trial with a controlled-release formulation of GABA, Remygen. Pharmacokinetics, glucose control and hormonal counter-regulatory response during hypoglycemic clamps were evaluated at every dose increase (200 mg, 600 mg and 1200 mg).Results: During the trial there were no serious and only a few, transient, adverse events reported. Without treatment, the counter-regulatory hormone response to hypoglycemia was severely blunted. Intake of 600 mg GABA more than doubled the glucagon, epinephrine, growth hormone and cortisol responses to hypoglycemia.Conclusions: We find that the GABA treatment was well tolerated and established a counter-regulatory response to hypoglycemia in long-standing T1D. Further studies regarding not only the clinical potential of Remygen for beta-cell regeneration but also its potential use as hypoglycemic prophylaxis are warranted. Trail registration number and EudraCT2018-001115-73.
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25. |
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26. |
- Espes, Daniel, et al.
(author)
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Increased Circulating Betatrophin Concentrations in Patients with Type 2 Diabetes
- 2014
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In: International Journal of Endocrinology. - : Hindawi Limited. - 1687-8337 .- 1687-8345. ; 2014, s. 323407-
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Journal article (peer-reviewed)abstract
- Betatrophin has recently been described as a key hormone to stimulate beta-cell mass expansion in response to insulin resistance and obesity in mice. The finding has generated an interest in the development of antidiabetic drugs with betatrophin as the active component. However, the circulating levels of betatrophin in patients with type 2 diabetes are not well known. Betatrophin concentrations in plasma of 27 type 2 diabetes patients and 18 gender-, age-, and BMI-matched controls were measured. Study participants were characterized with regard to BMI, waist and hip circumference, blood pressure, and fasting plasma blood lipids, creatinine, glucose, HbA1c, and C-peptide. HOMA2 indices were calculated. Betatrophin was 40% higher in patients with type 2 diabetes (893 +/- 80 versus 639 +/- 66 pg/mL). Betatrophin positively correlated with age in the controls and with HbA1c in the type 2 diabetes patients. All study participants were insulin resistant with mean HOMA2B IR in both groups exceeding 2 and HOMA2% S < 50%. Control individuals had impaired fasting glucose concentrations. In this report on betatrophin concentrations in type 2 diabetes and insulin resistance, elevated betatrophin levels were measured in the patients with type 2 diabetes. Future studies are clearly needed to delineate the exact role, if any, of betatrophin in regulating human beta-cell mass.
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27. |
- Espes, Daniel, et al.
(author)
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Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes
- 2014
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 57:1, s. 50-53
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Journal article (peer-reviewed)abstract
- Aims/hypothesis The hormone betatrophin was recently described as a potent stimulator of beta cell proliferation in mice. Insulin resistance, but not insulin deficiency, caused upregulation of betatrophin expression. If these findings were found to be fully applicable in humans, this would open up the possibility of future betatrophin treatment in type 1 diabetes. The present study measured for the first time betatrophin concentrations in humans and tested the hypothesis that there would be no difference in circulating betatrophin concentrations between patients with type 1 diabetes and healthy individuals. Methods Betatrophin concentrations in plasma of 33 patients with type 1 diabetes and 24 age-matched healthy controls were measured by ELISA. The study participants were characterised for blood lipids, BMI, plasma glucose and HbA(1c), and, for the diabetic patients, their insulin requirements and any residual C-peptide concentrations. Results Plasma betatrophin concentrations were normally similar to 300 pg/ml, but were approximately doubled in patients with type 1 diabetes. In the patients, there were no correlations between betatrophin and age, blood lipids, BMI, glucose control or insulin requirement, whereas in controls betatrophin levels increased with age. BMI, blood pressure and triacylglycerol, LDL-cholesterol and HDL-cholesterol levels were similar in patients and healthy controls. Conclusions/interpretation Circulating concentrations of betatrophin are increased in type 1 diabetes in contrast with what was recently described in an insulin-deficient mouse model. However, increased betatrophin concentrations do not protect against loss of C-peptide. Betatrophin treatment in type 1 diabetes would therefore probably not be successful without the use of supraphysiological doses or a combination with immune regulatory treatment.
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28. |
- Espes, Daniel, 1985-, et al.
(author)
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Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide
- 2017
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 40:8, s. 1090-1095
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Journal article (peer-reviewed)abstract
- OBJECTIVE Many patients with long-standing type 1 diabetes have remaining functional β-cells. This study investigated immunological differences between patients with or without measurable remaining endogenous insulin production after ≥10 years duration of disease.RESEARCH DESIGN AND METHODS Patients (n = 113; ≥18 years of age) with type 1 diabetes and with disease duration of ≥10 years were recruited at Uppsala University Hospital. Residual β-cell function was determined with an ultrasensitive C-peptide ELISA. Circulating cytokines, including interleukin-35 (IL-35), were determined in plasma. Additional blood samples were collected from 14 of the identified C-peptide–positive patients and 12 of the C-peptide–negative patients, as well as from 15 healthy control subjects, and were used for immediate investigation of peripheral blood mononuclear cells.RESULTS The blood concentration of the cytokine IL-35 was markedly lower in C-peptide–negative patients, and this was associated with a simultaneous decrease in the proportion of IL-35+ regulatory T cells (Tregs), IL-35+ regulatory B cells, and IL-35–producing CD8+Foxp3+ cells. IL-35 has previously been shown to maintain the phenotype of Tregs, block the differentiation of T-helper 17 cells, and thereby dampen immune assaults to β-cells. We found that the proportions of IL-17a+ cells among the Tregs, CD4+ T cells, and CD8+ T cells were lower in the C-peptide–positive patients.CONCLUSIONS Patients with remaining endogenous β-cell function after >10 years duration of type 1 diabetes differ immunologically from other patients with long-standing type 1 diabetes. In particular, they have a much higher IL-35 production.
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29. |
- Espes, Daniel, et al.
(author)
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Increased levels of irisin in people with long-standing Type1 diabetes
- 2015
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In: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 32:9, s. 1172-1176
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Journal article (peer-reviewed)abstract
- BackgroundIrisin stimulates browning of white adipose tissue and improves metabolic control in mice. Betatrophin, another recently described hormone, improves metabolic control in mice by inducing -cell proliferation. Invitro, irisin stimulates the expression of betatrophin in rat adipocytes. There is a great interest in developing drugs that target or use these hormones for the treatment of obesity and diabetes. We have previously reported on increased levels of betatrophin in people with Type1 diabetes, but the levels of irisin are currently unknown. AimTo characterize the levels of irisin in Type1 diabetes and investigate a potential correlation with betatrophin. MethodsIrisin and betatrophin were measured by enzyme-linked immunosorbant assay (ELISA) in 45 individuals with Type1 diabetes and in 25 healthy controls. ResultsIrisin levels were increased in people with Type1 diabetes, and especially in women. Negative correlations between irisin levels and age at onset of Type1 diabetes and plasma triacylglycerol levels were observed. Interestingly, in women with Type1 diabetes a negative correlation between irisin and insulin doses was also observed. When computing correlations for all study participants, a positive correlation between irisin and total betatrophin was observed, but not between irisin and full-length betatrophin. ConclusionWe report on increased circulating levels of irisin in people with Type1 diabetes, especially in women. For women with Type1 diabetes, the levels of irisin correlated with lower insulin requirements. Further studies are clearly needed to determine the role of irisin in Type1 diabetes.
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30. |
- Espes, Daniel, 1985-, et al.
(author)
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Longitudinal Assessment of 11C-5-Hydroxytryptophan Uptake in Pancreas After Debut of Type 1 Diabetes
- 2021
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 70:4, s. 966-975
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Journal article (peer-reviewed)abstract
- The longitudinal alterations of the pancreatic β-cell and islet mass in the progression of type 1 diabetes (T1D) are still poorly understood. The objective of this study was to repeatedly assess the endocrine volume and the morphology of the pancreas for up to 24 months after T1D diagnosis (n = 16), by 11C-5-hydroxytryptophan (11C-5-HTP) positron emission tomography (PET) and MRI. Study participants were examined four times by PET/MRI: at recruitment and then after 6, 12, and 24 months. Clinical examinations and assessment of β-cell function by a mixed-meal tolerance test and fasting blood samples were performed in connection with the imaging examination. Pancreas volume has a tendency to decrease from 50.2 ± 10.3 mL at T1D debut to 42.2 ± 14.6 mL after 24 months (P < 0.098). Pancreas uptake of 11C-5-HTP (e.g., the volume of the endocrine pancreas) did not decrease from T1D diagnosis (0.23 ± 0.10 % of injected dose) to 24-month follow-up, 0.21 ± 0.14% of injected dose, and exhibited low interindividual changes. Pancreas perfusion was unchanged from diagnosis to 24-month follow-up. The pancreas uptake of 11C-5-HTP correlated with the long-term metabolic control as estimated by HbA1c (P < 0.05). Our findings argue against a major destruction of β-cell or islet mass in the 2-year period after diagnosis of T1D.
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31. |
- Espes, Daniel, 1985-, et al.
(author)
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Pancreatic perfusion and its response to glucose as measured by simultaneous PET/MRI
- 2019
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In: Acta Diabetologica. - : Springer. - 0940-5429 .- 1432-5233. ; 56:10, s. 1113-1120
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Journal article (peer-reviewed)abstract
- 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.
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32. |
- Espes, Daniel, 1985-, et al.
(author)
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Pregnancy induces pancreatic insulin secretion in women with long-standing type 1 diabetes
- 2022
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In: BMJ Open Diabetes Research & Care. - : BMJ Publishing Group Ltd. - 2052-4897. ; 10:6
-
Journal article (peer-reviewed)abstract
- Introduction: Pregnancy entails both pancreatic adaptations with increasing beta-cell mass and immunological alterations in healthy women. In this study, we have examined the effects of pregnancy on beta-cell function and immunological processes in long-standing type 1 diabetes (L-T1D).Research design and methods: Fasting and stimulated C-peptide were measured after an oral glucose tolerance test in pregnant women with L-T1D (n=17) during the first trimester, third trimester, and 5-8 weeks post partum. Two 92-plex Olink panels were used to measure proteins in plasma. Non-pregnant women with L-T1D (n=30) were included for comparison.Results: Fasting C-peptide was detected to a higher degree in women with L-T1D during gestation and after parturition (first trimester: 64.7%, third trimester: 76.5%, and post partum: 64.7% vs 26.7% in non-pregnant women). Also, total insulin secretion and peak C-peptide increased during pregnancy. The plasma protein levels in pregnant women with L-T1D was dynamic, but few analytes were functionally related. Specifically, peripheral levels of prolactin (PRL), prokineticin (PROK)-1, and glucagon (GCG) were elevated during gestation whereas levels of proteins related to leukocyte migration (CCL11), T cell activation (CD28), and antigen presentation (such as CD83) were reduced.Conclusions: In summary, we have found that some C-peptide secretion, that is, an indirect measurement of endogenous insulin production, is regained in women with L-T1D during pregnancy, which might be attributed to elevated peripheral levels of PRL, PROK-1, or GCG.
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33. |
- Espes, Daniel, et al.
(author)
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Quantification of Beta-Cell Mass in Intramuscular Islet Grafts using Radiolabeled Exendin-4
- 2016
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In: Transplantation Direct. - 2373-8731. ; 2:8
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Journal article (peer-reviewed)abstract
- Background: There is an increasing interest in alternative implantation sites to the liver for islet transplantation. Intramuscular implantation has even been tested clinically. Possibilities to monitor [beta]-cell mass would be of huge importance not only for the understanding of islet engraftment but also for the decision of changing the immunosuppressive regime. We have therefore evaluated the feasibility of quantifying intramuscular [beta]-cell mass using the radiolabeled glucagon like peptide-1 receptor agonist DO3A-VS-Cys40-Exendin-4.Methods: One hundred to 400 islets were transplanted to the abdominal muscle of nondiabetic mice. After 3 to 4 weeks, 0.2 to 0.5 MBq [177Lu]DO3A-VS-Cys40-Exendin-4 was administered intravenously. Sixty minutes postinjection abdominal organs and graft bearing muscle were retrieved, and the radioactive uptake measured in a well counter within 10 minutes. The specific uptake in native and transplanted islets was assessed by autoradiography. The total insulin-positive area of the islet grafts was determined by immunohistochemistry.Results: Intramuscular islet grafts could easily be visualized by this tracer, and the background uptake was very low. There was a linear correlation between the radioactivity uptake and the number of transplanted islets, both for standardized uptake values and the total radiotracer uptake in each graft (percentage of injected dose). The quantified total insulin area of surviving [beta] cells showed an even stronger correlation to both standardized uptake values (R = 0.96, P = 0.0002) and percentage of injected dose (R = 0.88, P = 0.0095). There was no correlation to estimated [alpha] cell mass.Conclusions: [177Lu]DO3A-VS-Cys40-Exendin-4 could be used to quantify [beta]-cell mass after experimental intramuscular islet transplantation. This technique may well be transferred to the clinical setting by exchanging Lutetium-177 radionuclide to a positron emitting Gallium-68.
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34. |
- Espes, Daniel, et al.
(author)
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Rapid Restoration of Vascularity and Oxygenation in Mouse and Human Islets Transplanted to Omentum May Contribute to Their Superior Function Compared to Intraportally Transplanted Islets
- 2016
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In: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 16:11, s. 3246-3254
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Journal article (peer-reviewed)abstract
- Transplantation of islets into the liver confers several site-specific challenges, including a delayed vascularization and prevailing hypoxia. The greater omentum has in several experimental studies been suggested as an alternative implantation site for clinical use, but there has been no direct functional comparison to the liver. In this experimental study in mice, we characterized the engraftment of mouse and human islets in the omentum and compared engraftment and functional outcome with those in the intraportal site. The vascularization and innervation of the islets transplanted into the omentum were restored within the first month by paralleled ingrowth of capillaries and nerves. The hypoxic conditions in the islets early posttransplantation were transient and restricted to the first days. Newly formed blood vessels were fully functional, and the blood perfusion and oxygenation of the islets became similar to that of endogenous islets. Furthermore, islet grafts in the omentum showed at 1 month posttransplantation functional superiority to intraportally transplanted grafts. We conclude that in contrast to the liver the omentum provides excellent engraftment conditions for transplanted islets. Future studies in humans will be of great interest to investigate the capability of this site to also harbor larger grafts without interfering with islet functionality.
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35. |
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36. |
- Espes, Daniel, et al.
(author)
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Severe diabetic ketoacidosis in combination with starvation and anorexia nervosa at onset of type 1 diabetes : A case report
- 2013
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In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 118:2, s. 130-133
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Journal article (peer-reviewed)abstract
- We here report a case of diabetic ketoacidosis at onset of type 1 diabetes after a prolonged period of starvation due to anorexia nervosa. A 53-year-old female with a history of anorexia nervosa was admitted to the psychiatric clinic due to psychotic behaviour and inability to take care of herself. Twenty-four hours after admission she was transferred to the clinic of internal medicine due to altered mental status, and laboratory screening revealed a pH of 6.895 and blood glucose concentration of 40 mmol/L. Due to the unusual combination of prolonged starvation and diabetic ketoacidosis we implemented some modifications of existing treatment guidelines and some special considerations regarding nutrition in order to prevent a re-feeding syndrome.
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37. |
- Espes, Daniel, et al.
(author)
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Striated Muscle as Implantation Site for Transplanted Pancreatic Islets
- 2011
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In: Journal of Transplantation. - : Hindawi Limited. - 2090-0007 .- 2090-0015. ; 2011, s. 352043-
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Research review (peer-reviewed)abstract
- Islet transplantation is an attractive treatment for selected patients with brittle type 1 diabetes. In the clinical setting, intraportal transplantation predominates. However, due to extensive early islet cell death, the quantity of islets needed to restore glucose homeostasis requires in general a minimum of two donors. Moreover, the deterioration of islet function over time results in few insulin-independent patients after five-year followup. Specific obstacles to the success of islet transplantation include site-specific concerns for the liver such as the instant blood mediated inflammatory reaction, islet lipotoxicity, low oxygen tension, and poor revascularization, impediments that have led to the developing interest for alternative implantation sites over recent years. Within preclinical settings, several alternative sites have now been investigated and proven favorable in various aspects. Muscle is considered a very promising site and has physiologically properties and technical advantages that could make it optimal for islet transplantation.
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38. |
- Espes, Daniel, 1985-, et al.
(author)
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Subkutant injicerat insulin kan ge amyloidinlagring: Diagnostiska dilemman och fallgropar för patologen och oanade konsekvenser för diabetologen : [Amyloid from insulin treatment: a pitfall for the pathologist and the diabetologist]
- 2020
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In: Läkartidningen. - : Läkartidningen Förlag. - 0023-7205 .- 1652-7518. ; 117
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Journal article (peer-reviewed)abstract
- Biopsies from six diabetic patients with subcutaneous amyloid deposits formed by injected insulin have been sent to our laboratory during the last year. In all but one of the six patients a subcutaneous adipose tissue biopsy was taken due to suspicion of systemic amyloidosis. Four of these patients had renal insufficiency, with monoclonal gammopathy of undetermined significance (MGUS) in three while the fifth had heredity for transthyretin amyloidosis. In the sixth patient a biopsy was taken due to subcutaneous nodules at insulin injection sites. In all biopsies, large amounts of amyloid were present and their biochemical nature was elucidated by immunohistochemistry or western blot. The risk of incorrect interpretation with misdiagnosis of systemic amyloidosis is underlined. The consequences this may have on insulin treatment are insufficiently studied.
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39. |
- Espes, Daniel, 1985-, et al.
(author)
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Towards the clinical translation of stem cell therapy for type 1 diabetes
- 2017
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In: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 177:4, s. R159-R168
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Research review (peer-reviewed)abstract
- Insulin-producing cells derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) have for long been a promising, but elusive treatment far from clinical translation into type 1 diabetes therapy. However, the field is now on the verge of moving such insulin-producing cells into clinical trials. Although stem cell therapies provide great opportunities, there are also potential risks such as teratoma formation associated with the treatment. Many considerations are needed on how to proceed with clinical translation, including whether to use hESCs or iPSCs, and whether encapsulation of tissue will be needed. This review aims to give an overview of the current knowledge of stem cell therapy outcomes in animal models of type 1 diabetes and a proposed road map towards the clinical setting with special focus on the potential risks and hurdles which needs to be considered. From a clinical point of view, transplantation of insulin-producing cells derived from stem cells must be performed without immune suppression in order to be an attractive treatment option. Although costly and highly labour intensive, patient-derived iPSCs would be the only solution, if not clinically successful encapsulation or tolerance induction protocols are introduced.
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40. |
- Grönberg, Annika, et al.
(author)
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Better HbA1c during the first years after diagnosis of type 1 diabetes is associated with residual C peptide 10 years later
- 2020
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In: BMJ Open Diabetes Research & Care. - : BMJ. - 2052-4897. ; 8
-
Journal article (peer-reviewed)abstract
- Objective: To identify the factors associated with residual C peptide production at least 10 years after diagnosis in children and adolescents with type 1 diabetes.Research design and methods: 73 children and adolescents (<25 years), born in 1988-2005, diagnosed with type 1 diabetes were included during the 4-year study period (2013-2016). At least 10 years after diagnosis, we measured any remaining C peptide concentration using an ultrasensitive C peptide ELISA (>= 1.17pmol/L). The average hemoglobin A1c (HbA1c) was calculated during each of the 10 years after diagnosis and further grand average was calculated for the entire study period.Results: C peptide was detectable in 38% of participants. The C peptide concentration was 4.35.3pmol/L. At onset of type 1 diabetes, participants were on average approximately 5years of age, and their average HbA1c was 9.4% (79mmol/mol). During the first 3years after diagnosis, HbA1c was lower in the group with detectable C peptide at follow-up >= 10 years later. Moreover, detectable C peptide was more common among female participants. Body mass index SD scores had not increased since the 1-year follow-up, but were higher in patients with measurable C peptide. Nine participants (12%) had been diagnosed with celiac disease and two (3%) with hypothyreosis. Eighteen (25%) participants had retinopathy.Conclusions: Children and adolescents with detectable C peptide after more than 10 years of diabetes duration were predominantly female and had better HbA1c than others during the first 3years after diagnosis.
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41. |
- Grönberg, Annika, et al.
(author)
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Higher risk of severe hypoglycemia in children and adolescents with a rapid loss of C-peptide during the first 6 years after type 1 diabetes diagnosis
- 2022
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In: BMJ Open Diabetes Research & Care. - : BMJ Publishing Group Ltd. - 2052-4897. ; 10
-
Journal article (peer-reviewed)abstract
- Introduction: The progression to insulin deficiency in type 1 diabetes is heterogenous. This study aimed to identify early characteristics associated with rapid or slow decline of beta-cell function and how it affects the clinical course.Research design and methods: Stimulated C-peptide was assessed by mixed meal tolerance test in 50 children (<18 years) during 2004-2017, at regular intervals for 6 years from type 1 diabetes diagnosis. 40% of the children had a rapid decline of stimulated C-peptide defined as no measurable C-peptide (<0.03 nmol/L) 30 months after diagnosis.Results: At diagnosis, higher frequencies of detectable glutamic acid decarboxylase antibodies (GADA) and IA-2A (p=0.027) were associated with rapid loss of beta-cell function. C-peptide was predicted positively by age at 18 months (p=0.017) and 30 months duration (p=0.038). BMI SD scores (BMISDS) at diagnosis predicted higher C-peptide at diagnosis (p=0.006), 3 months (p=0.002), 9 months (p=0.005), 30 months (p=0.022), 3 years (p=0.009), 4 years (p=0.016) and 6 years (p=0.026), whereas high HbA1c and blood glucose at diagnosis predicted a lower C-peptide at diagnosis (p=<0.001) for both comparisons. Both GADA and IA-2A were negative predictors of C-peptide at 9 months (p=0.011), 18 months (p=0.008) and 30 months (p<0.001). Ten children had 22 events of severe hypoglycemia, and they had lower mean C-peptide at 18 months (p=0.025), 30 months (p=0.008) and 6 years (p=0.018) compared with others. Seven of them had a rapid decline of C-peptide (p=0.030), and the odds to experience a severe hypoglycemia were nearly fivefold increased (OR=4.846, p=0.04).Conclusions: Low age and presence of multiple autoantibodies at diagnosis predicts a rapid loss of beta-cell function in children with type 1 diabetes. Low C-peptide is associated with an increased risk of severe hypoglycemia and higher Hemoglobin A1C. A high BMISDS at diagnosis is predictive of remaining beta-cell function during the 6 years of follow-up.
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42. |
- Hill, Henrik, et al.
(author)
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Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes
- 2022
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In: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:1
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Journal article (peer-reviewed)abstract
- Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. GABA is gaining increasing interest in diabetes research due to its immune-modulatory and beta-cell stimulatory effects and is a highly interesting drug candidate for the treatment of type 1 diabetes (T1D). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), one of the targets for autoantibodies linked to T1D. Using mass spectrometry, we have quantified the endogenous circulating levels of GABA in patients with new-onset and long-standing T1D and found that the levels are unaltered when compared to healthy controls, i.e., T1D patients do not have a deficit of systemic GABA levels. In T1D, GABA levels were negatively correlated with IL-1 beta, IL-12, and IL-15 15 and positively correlated to levels of IL-36 beta and IL-37. Interestingly, GABA levels were also correlated to the levels of GAD-autoantibodies. The unaltered levels of GABA in T1D patients suggest that the GABA secretion from beta-cells only has a minor impact on the circulating systemic levels. However, the local levels of GABA could be altered within pancreatic islets in the presence of GAD-autoantibodies.
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43. |
- Hill, Henrik, et al.
(author)
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Real-life data of hypoglycemic events in children and adolescents with type 1 diabetes
- 2023
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In: BMJ Open Diabetes Research & Care. - : BMJ. - 2052-4897. ; 11:5
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Journal article (peer-reviewed)abstract
- Introduction: Hypoglycemia composes an always present risk in the treatment of type 1 diabetes (T1D) and can be a fatal complication. Many studies on hypoglycemic events are based on self-reported data or focused on the aggregated time below range. We have processed continuous glucose monitoring (CGM) data in children and adolescents with T1D in order to examine all occurring hypoglycemic events.Research design and methods: CGM data (mean 168 +/- 3 days) from 214 children and adolescents with T1D were analyzed using computer-based algorithms. Patients were divided into three groups based on estimated HbA1c (eHbA1c): (1) <= 48 mmol/mol (n=58); (2) 49-64 mmol/ mol (n=113); (3) >= 65 mmol/mol (n=43). The groups were compared concerning descriptive data and CGM metrics with emphasis on the frequency of hypoglycemic events.Results: Only one self-reported event of severe hypoglycemia was registered, while 54 390 hypoglycemic events (<3.9 mmol/L (<70 mg/dL)) were identified from CGM data out of which 11 740 were serious (<3.0 mmol/L (<54 mg/dL)). On average there were 1.5 +/- 0.1 hypoglycemic events per 24 hours out of which 1.2 +/- 0.1 were mild (3.0-3.9 mmol/L) and 0.3 +/- 0.02 serious. Group 1 had a higher frequency of both total and mild hypoglycemic events compared with both groups 2 and 3. However, the frequency of serious hypoglycemic events was similar in all groups. A negative correlation was observed for eHbA1c and total daily and mild hypoglycemic events (r=-0.57 and r=-0.66, respectively, p<0.0001), whereas for serious hypoglycemic events there was only a borderline significance (r=-0.13, p=0.05).Conclusions: This study shows that hypoglycemic events are a frequent phenomenon in children and adolescents with T1D, occurring regardless of overall metabolic control. Although patients with an HbA1c =48 mmol/mol had a higher frequency of mild hypoglycemic events there was no increase in serious hypoglycemic events.
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44. |
- Jansson, Leif, et al.
(author)
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Pancreatic islet blood flow and its measurement
- 2016
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In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 121:2, s. 81-95
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Research review (peer-reviewed)abstract
- Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting beta-cells, endothelium derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.
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45. |
- Katsogiannos, Petros, 1979-, et al.
(author)
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Changes in Circulating Cytokines and Adipokines After RYGB in Patients with and without Type 2 Diabetes
- 2021
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In: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 29:3, s. 535-542
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Journal article (peer-reviewed)abstract
- ObjectiveThis study aimed to compare cytokine and adipokine levels in patients with obesity with and without type 2 diabetes (T2D) at baseline and 6 months after Roux‐en‐Y gastric bypass (RYGB) with healthy controls.MethodsA total of 34 patients (21 with T2D) with BMI of 30 to 45 kg/m2 were compared with 25 healthy controls without obesity. Cytokines, adipokines, and peptides of relevance for inflammation and metabolism were analyzed in plasma.ResultsSignificant decreases in weight and glycated hemoglobin A1c were observed. At baseline, interleukin‐6 (IL‐6), IFN‐β, IL‐18, leptin, and hepatocyte growth factor were higher in all patients with obesity compared with healthy controls. In patients without T2D, TNF‐α, IL‐1α, IL‐2, IL‐15, and visfatin were also increased, whereas bone morphogenic protein‐4 was decreased. Following RYGB, IL‐6 and hepatocyte growth factor were still increased in both groups compared with controls. In T2D patients, IFN‐β, IL‐27, IL‐1α, IL‐2, regenerating islet‐derived protein 3A, visfatin, and osteopontin were found to be increased. In patients without T2D, TNF‐α, IL‐1α, IL‐2, IL‐15, leptin, and visfatin remained increased.ConclusionsThe altered cytokine profile of patients with obesity persisted after RYGB despite large weight loss and improved metabolic status, thus reflecting an inherent inflammatory state.
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46. |
- Katsogiannos, Petros, et al.
(author)
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Rapid changes in neuroendocrine regulation may contribute to reversal of type 2 diabetes after gastric bypass surgery
- 2020
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In: Endocrine. - : SPRINGER. - 1355-008X .- 1559-0100. ; 67:2, s. 344-353
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Journal article (peer-reviewed)abstract
- Objective: To explore the role of hormones and the autonomic nervous system in the rapid remission of diabetes after Roux-en-Y Gastric Bypass (RYGB).Research design and methods: Nineteen obese patients with type 2 diabetes, 7 M/12 F, were randomized (2:1) to RYGB or standard-of-care medical treatment (control). At baseline and 4 and 24 weeks post surgery, fasting blood sampling, OGTT, intravenous arginine challenge, and heart-rate variability (HRV) assessments were performed.Results: At both 4 and 24 weeks post-RYGB the following effects were found: arginine-stimulated insulin secretion was reduced. GLP-1, GIP, and glucagon rise during OGTT was enhanced. IGF-1 and GH levels increased. In addition, total HRV and spectral components P-LF (power of low frequency) and P-HF (power of high frequency) increased. At 4 weeks, morning cortisol was lower than baseline and 24 weeks. At 24 weeks, NEFA levels during OGTT, and the P-LF/P-HF ratio decreased. None of these changes were seen in the control group.Conclusions: There were rapid changes within 4 weeks after RYGB: signs of enhanced parasympathetic nerve activity, reduced morning cortisol, and enhanced incretin and glucagon responses to glucose. The findings suggest that neurohormonal mechanisms can contribute to the rapid improvement of insulin resistance and glycemia following RYGB in type 2 diabetes.
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47. |
- Korol, Sergiy V, et al.
(author)
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Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells
- 2018
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In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 30
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Journal article (peer-reviewed)abstract
- In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors in human islet β cells as biological sensors and reveal that 100-1000nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABAA receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D.
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48. |
- Liljebäck, Hanna, et al.
(author)
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Unsurpassed Intrahepatic Islet Engraftment : the Quest for New Sites for Beta Cell Replacement
- 2019
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In: Cell Medicine. - : Sage Publications. - 2155-1790. ; 11
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Journal article (other academic/artistic)abstract
- The liver is currently the site of choice for clinical islet transplantation, even though many alternative implantation sites have lately been proposed as more ideal for graft survival. The suggested sites, for example intramuscular space, omentum, bone marrow, and spleen, are sometimes difficult to compare due to differences in animal model, islet isolation procedure, and islet quality. In addition, the variation in transplanted islet mass is vast. The aim of this commentary is to review alternative implantation sites tested experimentally as well as in clinical islet transplantation. Although many sites have been investigated, none have convincingly proved better suited for clinical islet transplantation than intraportal injection to the liver, regardless of whether it is autologous or allogeneic transplantation. However, in order to fully evaluate upcoming bioengineering techniques, such as scaffolds containing insulin-producing cells derived from stem cells, the need of an alternative site has arisen to enable cellular monitoring, which currently cannot be achieved within the liver.
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49. |
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50. |
- Lundkvist, Per, et al.
(author)
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Predictive biomarkers of rapidly developing insulin deficiency in children with type 1 diabetes
- 2024
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In: BMJ Open Diabetes Research & Care. - : BMJ Publishing Group Ltd. - 2052-4897. ; 12:1
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Journal article (peer-reviewed)abstract
- Introduction The rate of progression to complete insulin deficiency varies greatly in type 1 diabetes. This constitutes a challenge, especially when randomizing patients in intervention trials aiming to preserve beta cell function. This study aimed to identify biomarkers predictive of either a rapid or slow disease progression in children with new-onset type 1 diabetes.Research design and methods A retrospective, longitudinal cohort study of children (<18 years) with type 1 diabetes (N=46) was included at diagnosis and followed until complete insulinopenia (C-peptide <0.03 nmol/L). Children were grouped into rapid progressors (n=20, loss within 30 months) and slow progressors (n=26). A sex-matched control group of healthy children (N=45) of similar age was included for comparison. Multiple biomarkers were assessed by proximity extension assay (PEA) at baseline and follow-up.Results At baseline, rapid progressors had lower C-peptide and higher autoantibody levels than slow. Three biomarkers were higher in the rapid group: carbonic anhydrase 9, corticosteroid 11-beta-dehydrogenase isozyme 1, and tumor necrosis factor receptor superfamily member 21. In a linear mixed model, 25 proteins changed over time, irrespective of group. One protein, a coxsackievirus B–adenovirus receptor (CAR) increased over time in rapid progressors. Eighty-one proteins differed between type 1 diabetes and healthy controls. Principal component analysis could not distinguish between rapid, slow, and healthy controls.Conclusions Despite differences in individual proteins, the combination of multiple biomarkers analyzed by PEA could not distinguish the rate of progression in children with new-onset type 1 diabetes. Only one marker was altered significantly when considering both time and group effects, namely CAR, which increased significantly over time in the rapid group. Nevertheless, we did find some markers that may be useful in predicting the decline of the C-peptide. Moreover, these could potentially be important for understanding type 1 diabetes pathogenesis.
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