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Background: Type 1 diabetes (T1D) is an autoimmune disease characterized by a progressive β-cell destruction. There are no clinically established methods for quantifying endocrine cells of the pancreas and current knowledge is almost exclusively based on autopsy material and functional measurements. Based on the expression of the γ-aminobutyric acid A receptors (GABA A Rs) in pancreatic islets and the fact that GABA A R agonists are being explored as treatment for T1D, we hypothesized that the positron emission tomography (PET) tracer [ 11 C]flumazenil ([ 11 C]FMZ) could serve as a marker of the endocrine mass of the pancreas. The in vivo uptake of [ 11 C]FMZ in pig pancreas was evaluated by PET/CT, either tracer alone or after blockade of GABA A R by unlabeled flumazenil. The pancreatic binding of [ 11 C]FMZ was investigated in vitro with frozen sections of pig pancreas as well as human organ donors, in addition to isolated mouse and human islets and exocrine preparations. The expression of GABA A R subunits in pig, human and mouse pancreas was explored by immunohistochemistry., Results: Strong specific in vivo uptake of [ 11 C]FMZ was observed in the pig brain as expected, but in the pancreas the signal was moderate and only partially reduced by blockade. In vitro experiments revealed a positive but weak and variable binding of [ 11 C]FMZ in islets compared to exocrine tissue in the mouse, pig and human pancreas. In pig and mouse pancreatic islets we identified the GABA A R subunits β2 and γ2 but not α2. In the human pancreas from non-diabetic donors, we have identified the α2, β2 (although weak) and γ2 subunits, whereas from a T2D donor the α2 subunit was missing., Conclusions: Our findings suggest that [ 11 C]FMZ bind to GABA A Rs in the islets, but not with a sufficient contrast or magnitude to be implemented as an in vivo PET marker for the endocrine mass of the pancreas. However, GABA A Rs with different subunits are widely expressed in the endocrine cells within the pancreas in pig, human and mouse. Hence, the GABA A R could still be a potential imaging target for the endocrine cells of the pancreas but would require tracers with higher affinity and selectivity for individual GABA A R subunits., Competing Interests: Declarations. Ethics approval and consent to participate: All animal procedures were performed in agreement with the Uppsala University guidelines for animal research (UFV 2007/724) and national legislations. The studies were planned and performed in according to the 3Rs principle and to the ARRIVE guidelines for animal research and were approved by the animal Research Ethical Committee of the Uppsala Region (Ethical approval # 5.8.18-15648/2019 for experiments with pig and dnr 5.8.18-03604 for experiments with mice). The use of human tissues from Uppsala Biobank (registration #827) was approved by the Regional Ethics Board of Uppsala, Sweden (now the Swedish Ethical Review Authority) (2011/473, Ups 02-577, 2015/401) and were collected and treated according to local institutional and Swedish national rules and regulations. Consent for publication: Not applicable. Competing interests: DE is co-founder and shareholder of OneTwo Analytics AB. OE is co-founder, employee and minority shareholder of Antaros Tracer AB. The remaining authors declare that they have no competing interest., (© 2024. The Author(s).)

Introduction: Despite the improvements in diabetes management by continuous glucose monitoring (CGM) it is difficult to capture the complexity of CGM data in one metric. We aimed to develop a clinically relevant multidimensional scoring model with the capacity to identify the most alarming CGM episodes and/or patients from a large cohort., Research Design and Methods: Retrospective CGM data from 2017 to 2020 available in electronic medical records were collected from n=613 individuals with type 1 diabetes (total 82 114 days). A scoring model was developed based on three metrics; glycemic variability percentage, low blood glucose index and high blood glucose index. Values for each dimension were normalized to a numeric score between 0-100. To identify the most representative score for an extended time period, multiple ways to combine the mean score of each dimension were evaluated. Correlations of the scoring model with CGM metrics were computed. The scoring model was compared with interpretations of a clinical expert board (CEB)., Results: The dimension of hypoglycemia must be weighted to be representative, whereas the other two can be represented by their overall mean. The scoring model correlated well with established CGM metrics. Applying a score of ≥80 as the cut-off for identifying time periods with a 'true' target fulfillment (ie, reaching all targets for CGM metrics) resulted in an accuracy of 93.4% and a specificity of 97.1%. The accuracy of the scoring model when compared with the CEB was high for identifying the most alarming CGM curves within each dimension of glucose control (overall 86.5%)., Conclusions: Our scoring model captures the complexity of CGM data and can identify both the most alarming dimension of glycemia and the individuals in most urgent need of assistance. This could become a valuable tool for population management at diabetes clinics to enable healthcare providers to stratify care to the patients in greatest need of clinical attention., Competing Interests: Competing interests: LC, P-OC and DE have co-founded the company OneTwo Analytics AB of which JD is an employee. OneTwo Analytics AB is developing a commercial product (PRIO Scoring) based on the results presented here., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Aims/hypothesis: Compromised pancreatic sympathetic innervation has been suggested as a factor involved in both immune-mediated beta cell destruction and endocrine dysregulation of pancreatic islets. To further explore these intriguing findings, new techniques for in vivo assessment of pancreatic innervation are required. This is a retrospective study that aimed to investigate whether the noradrenaline (norepinephrine) analogue 11 C-hydroxy ephedrine ( 11 C-HED) could be used for quantitative positron emission tomography (PET) imaging of the sympathetic innervation of the human pancreas., Methods: In 25 individuals with type 2 diabetes and 64 individuals without diabetes, all of whom had previously undergone 11 C-HED-PET/CT because of pheochromocytoma or paraganglioma (or suspicion thereof), the 11 C-HED standardised uptake value (SUV mean ), 11 C-HED specific binding index (SBI), pancreatic functional volume (FV, in ml), functional neuronal volume (FNV, calculated as SUV mean  × FV), specific binding index with functional volume (SBI FV, calculated as SBI × FV) and attenuation on CT (HU) were investigated in the entire pancreas, and additionally in six separate anatomical pancreatic regions., Results: Generally, 11 C-HED uptake in the pancreas was high, with marked individual variation, suggesting variability in sympathetic innervation. Moreover, pancreatic CT attenuation (HU) (p<0.001), 11 C-HED SBI (p=0.0049) and SBI FV (p=0.0142) were lower in individuals with type 2 diabetes than in individuals without diabetes, whereas 11 C-HED SUV mean (p=0.15), FV (p=0.73) and FNV (p=0.30) were similar., Conclusions/interpretation: We demonstrate the feasibility of using 11 C-HED-PET for non-invasive assessment of pancreatic sympathetic innervation in humans. These findings warrant further prospective evaluation, especially in individuals with theoretical defects in pancreatic sympathetic innervation, such as those with type 1 diabetes., (© 2023. The Author(s).)

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., Competing Interests: Competing interests: DE is a co-founder of and shareholder in OneTwo Analytics. PK is employed by and a shareholder in OneTwo Analytics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 Δ-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., Trial Registration: ClinicalTrials.gov NCT03406585 FUNDING: The sponsor of the clinical trial is NextCell Pharma AB, Stockholm, Sweden., (© 2023. The Author(s).)

Introduction: To 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., Methods: CGM/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., Results: Of 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., Conclusions: The 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., (© 2023. The Author(s).)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Pregnancy entails both pancreatic adaptations with increasing β-cell mass and immunological alterations in healthy women. In this study, we have examined the effects of pregnancy on β-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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Different from traditional transport systems, such as cars or trains, which are limited by land transit space, flying cars (such as UAS, drones, and air taxis) do not occupy space with traffic. They have a degree of freedom in space and time, smaller displacement, and consequently, less stress for their users. Large companies and researchers around the world are working with different architectures, algorithms, and techniques to test air taxi transport to serve a significant proportion of people safely and autonomously. One of the main issues surrounding the diffusion of air taxis is safety and security, since a simple failure can lead to the loss of high-value assets, loss of the vehicle, and/or injuries to human lives, including fatalities. In this sense, despite significant efforts, the literature is still specific and limited regarding air taxi safety and security. Therefore, this study aimed to carry out an extensive systematic literature review of the main modern advances in techniques, architectures, and research carried out around the world focused on these types of vehicles. More than 210 articles from between 2015 and January 2022 were individually reviewed. In addition, this study also presents gaps that could serve as a direction for future research. As far as the authors are aware, no other study performs this type of review focused on air taxi safety.

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 (~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., (© 2021 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

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 α- and β-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.

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.

The anti-inflammatory role of regulatory B cells (Breg cells) has been associated with IL-35 based on studies of experimental autoimmune uveitis and encephalitis. The role of Breg cells and IL-35 + Breg cells for type 1 diabetes (T1D) remains to be investigated. We studied PBMCs from T1D subjects and healthy controls (HC) and found lowered proportions of Breg cells and IL-35 + Breg cells in T1D. To elucidate the role of Breg cells, the lymphoid organs of two mouse models of T1D were examined. Lower proportions of Breg cells and IL-35 + Breg cells were found in the animal models of T1D compared with control mice. In addition, the systemic administration of recombinant mouse IL-35 prevented hyperglycemia after multiple low dose streptozotocin (MLDSTZ) injections and increased the proportions of Breg cells and IL-35 + Breg cells. A higher proportion of IFN-γ + cells among Breg cells were found in the PBMCs of the T1D subjects. In the MLDSTZ mice, IL-35 administration decreased the proportions of IFN-γ + cells among the Breg cells. Our data illustrate that Breg cells may play an important role in the development of T1D and that IL-35 treatment prevents the development of hyperglycemia by maintaining the phenotype of the Breg cells under an experimental T1D condition.

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: NCT03635437 and EudraCT2018-001115-73., Competing Interests: Competing interests: DE and P-OC are listed as coinventors for a patent application submitted by Diamyd Medical, but do not have any financial interests in Diamyd Medical. None of the other authors have any conflicts of interest to declare., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 11 C-5-hydroxytryptophan ( 11 C-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 11 C-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 11 C-5-HTP correlated with the long-term metabolic control as estimated by HbA 1c ( 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., (© 2021 by the American Diabetes Association.)

Objective: This 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., Methods: A total of 34 patients (21 with T2D) with BMI of 30 to 45 kg/m 2 were compared with 25 healthy controls without obesity. Cytokines, adipokines, and peptides of relevance for inflammation and metabolism were analyzed in plasma., Results: Significant decreases in weight and glycated hemoglobin A 1c 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., Conclusions: The altered cytokine profile of patients with obesity persisted after RYGB despite large weight loss and improved metabolic status, thus reflecting an inherent inflammatory state., (© 2021 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)

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., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite that autoimmune diseases share similar immunogenetic mechanisms, studies comparing the protein composition in peripheral blood from patients with autoimmune endocrine diseases are limited. In this study, we applied proximity extension assay to measure proteins related to signaling and interactions within the immune system in peripheral blood from patients with new-onset (N-T1D) and long-standing (L-T1D) type 1 diabetes, Hashimoto's thyroiditis (HT), Graves' disease (GD), and autoimmune Addison's disease in addition to healthy controls (HC). Proteins in plasma and supernatants from cultured PBMC were measured by using a 92-plex Olink® INFLAMMATION panel. Soluble CDCP1 was more abundant in plasma from patients with N-T1D, L-T1D, HT, and GD than in HC. The L-T1D and HT groups had elevated plasma levels of SLAMF1 compared with HC. Patients and HC could not be distinguished by their protein composition in PBMC supernatants. The high-throughput multiplex technology enabled us to detect two low-abundant proteins that have been gradually connected to autoimmune diseases. Our study provides novel associations between CDCP1, SLAMF1, and autoimmune endocrine diseases, which might reflect a higher degree of inflammation and lymphocyte activation., (Copyright © 2020 Magnusson, Espes, Casas and Carlsson.)

Differences in pancreatic islet susceptibility during type 1 diabetes development may be explained by interislet variations. This study aimed to investigate if heterogeneities in vascular support and metabolic activity in rat and human islets may explain why some islets are attacked earlier than other islets. In rats, highly blood perfused islets were identified by injection of microspheres into the ascending aorta, whereas a combination of anterograde and retrograde injections of microspheres into pancreas was used to determine the islet vascular drainage system. Highly blood perfused islets had superior function and lower glucose threshold for insulin release when compared with other islets. These islets had a preferential direct venous drainage to the portal vein, whereas other islets mainly were incorporated into the exocrine capillary system. In BioBreeding rats, the hypothesis that islets with high islet blood perfusion was more prone to immune cell infiltration was investigated. Indeed, highly blood perfused islets were the first affected by the immune attack. In human subjects, differences in glucose threshold for insulin (C-peptide) secretion was evaluated in individuals recently diagnosed for type 1 diabetes and compared to control subjects. A preferential loss of capacity for insulin release in response to low glucose concentrations was observed at debut of type 1 diabetes. Our study indicates that highly blood perfused islets with direct venous drainage and lower glucose threshold for insulin release are of great importance for normal glucose homeostasis. At the same time, these highly metabolically active islets were the primary target of the immune system., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Although there is evidence that autoimmune diseases share similar immunogenetic mechanisms, studies comparing peripheral CD45 + cells from patients with autoimmune endocrine diseases in parallel are limited. In this study, we applied high-dimensional single-cell mass cytometry to phenotypically characterize PBMC from patients with new-onset (N-T1D) and long-standing type 1 diabetes, Hashimoto's thyroiditis (HT), Graves' disease and autoimmune Addison's disease (AD), as well as healthy controls. The frequency of CD20 lo CD27 hi CD38 hi HLA-DR int plasmablasts, CD86 + CD14 lo CD16 + non-classical monocytes and two subsets of CD56 dim HLA-DR + IFN-γ + NK cells were increased in patients with HT. Subsets of CD56 dim CD69 + HLA-DR - NK cells and CD8 + TEMRA cells, both expressing IFN-γ, were expanded and reduced, respectively, in the N-T1D group. In addition, patients with AD were characterized by an increased percentage of central memory CD8 + T cells that expressed CCR4, GATA3, and IL-2. We demonstrate that patients with N-T1D, HT, and AD had altered frequencies of distinct subsets within antigen-presenting and cytotoxic cell lineages. Previously unreported alterations of specific cell subsets were identified in samples from patients with HT and AD. Our study might contribute to a better understanding of shared and diverging immunological features between autoimmune endocrine diseases., (Copyright © 2020 Magnusson, Barcenilla, Pihl, Bensing, Espes, Carlsson and Casas.)

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.

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 (≥1.17 pmol/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 4.3±5.3 pmol/L. At onset of type 1 diabetes, participants were on average approximately 5 years of age, and their average HbA1c was 9.4% (79 mmol/mol). During the first 3 years 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 3 years after diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

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-( 18 F)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., Competing Interests: The authors declare no conflict of interest.

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.

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 [ 15 O]H 2 O 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 [ 15 O]H 2 O PET, IVIM MRI, and microspheres, respectively. There was a correlation between pancreatic perfusion as assessed by [ 15 O]H 2 O PET and IVIM MRI (r = 0.81, R 2  = 0.65, p < 0.01). The absolute quantification of pancreatic perfusion (ml/min/g) by [ 15 O]H 2 O PET was within a 15% error of margin of the microsphere technique., Conclusion: Pancreatic perfusion by [ 15 O]H 2 O PET was in agreement with the microsphere technique assessment. The IVIM MRI method has the potential to replace [ 15 O]H 2 O PET if the pancreatic perfusion is sufficiently large, but not when absolute quantitation is required.

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., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

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 .

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 Ca2+ channels in the plasma membrane are the voltage-gated Ca2+ (CaV) channels. We examined if a change in immunological tolerance is accompanied by altered ORAI, STIM and CaV 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 CaV2.3 gene was up-regulated in pregnancy and type 1 diabetes whereas the CaV 2.1 and CaV3.2 genes were up-regulated only in pregnancy and the CaV1.3 gene in type 1 diabetes. The results are consistent with that expression of ORAI, STIM and CaV 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., Competing Interests: The authors have declared that no competing interests exist.

Macroencapsulation devices provide the dual possibility of immunoprotecting 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 into patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155 000-180 000 islet equivalents (ie, 1800-4600 islet equivalents 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 (Clinicaltrials.gov: NCT02064309)., (© 2018 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

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 GABA A 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. GABA A 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 GABA A receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 German Center for Neurodegenerative Diseases (DZNE). Published by Elsevier B.V. All rights reserved.)

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., (© 2017 European Society of Endocrinology.)

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., (© 2017 by the American Diabetes Association.)