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The aim of this study was to assess the effect of four isocaloric meals with different macronutrient compositions on postprandial blood glucose, lipids, and glucagon in adults with type 1 diabetes (T1D). Seventeen subjects tested four isocaloric meals in a randomized crossover design. The meal compositions were as follows: high-carbohydrate (HC); high-carbohydrate with extra fiber (HC-fiber); low-carbohydrate high-protein (HP); and low-carbohydrate high-fat (HF). Blood glucose and lipid measurements were collected up to 4 h and glucagon up to 3 h postprandially. Mean postprandial glucose excursions were lower after the HP compared to the HC (p = 0.036) and HC-fiber meals (p = 0.002). There were no differences in mean glucose excursions after the HF meal compared to the HC and HP meals. The HF meal resulted in higher triglyceride excursions compared to the HP meal (p < 0.001) but not compared to the HC or HC-fiber meals. Glucagon excursions were higher at 180 min after the HP meal compared to the HC and HF meals. In conclusion, the low-carbohydrate HP meal showed the most favorable glycemic and metabolic effects during a 4 h postprandial period in subjects with T1D.

Supplementary Figure 1 from Hypoxia-Inducible Factor-1α and Hypoxia-Inducible Factor-2α Are Expressed in Kaposi Sarcoma and Modulated by Insulin-like Growth Factor-I

Purpose: Neoangiogenesis is essential for tumor development. Hypoxia-inducible factor (HIF), a transcriptional factor composed of two subunits (α and β), plays a key role in this process, activating proangiogenic factors such as vascular endothelial growth factor (VEGF). The HIF α subunits are critically regulated by oxygen and are also modulated by growth factors. Kaposi sarcoma (KS) is a highly vascular tumor that releases large amounts of VEGF and for which we have recently described an essential role for the insulin-like growth factor (IGF) system. We therefore investigated the expression of HIF α subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line.Results: Both HIF-1α and HIF-2α were expressed in KS biopsies in all tumoral stages. HIF-1α immunopositivity increased through the tumor development with highest expression in the late nodular stages. In KSIMM cells, IGF-I induced accumulation of both HIF α subunits. The induction suggests a translation mechanism as documented by cycloheximide chase experiment coupled with constant RNA levels as evaluated by quantitative real-time PCR. IGF-I–induced HIF α accumulation was followed by an increase in HIF function as assessed both by reporter gene assay and by induction of endogenous target gene expression (VEGF-A). Specific blockade of IGF-I receptor with αIR3 antibody or with picropodophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I–dependent induction of both HIF α congeners.Conclusion: These novel findings show the coupling between the IGF and HIF signaling in KS and suggest a coordinated contribution by these pathways to the characteristic vascular phenotype of this tumor.

The 5:2 diet, a type of intermittent fasting has recently gained popularity. The aim was to evaluate the feasibility and effects of the 5:2 diet for six months on weight, metabolic and hormonal risk factors for cardiovascular disease (CVD) in overweight subjects with and without type 2 diabetes (T2D). 97 (59 women) subjects, 35 with T2D and 62 without T2D (controls) followed the 5:2 diet (two days/week on a 500 (women) or 600 (men) kcal menu) for six months. Only 4/97 subjects discontinued. A weight loss of 4.2 (5.0–3.3) kg (4.94%) and 5.3 (6.4–4.2) kg (6.43%) was observed in controls and T2D, respectively. In both groups there were decreases in waist circumference, fat percentage, and blood pressure. Waist circumference decreased more in T2D compared to the controls. HbA1c improved in the T2D group. Metabolic control, lipids, adiponectin and leptin improved. Age-adjusted IGF-I decreased in the controls and IGF binding protein-1 increased in the T2D group suggesting improved hepatic insulin sensitivity in T2D. The 5:2 diet was feasible for 6 months and resulted in significant weight loss and improvement in metabolic and hormonal risk factors for CVD in overweight and obese subjects with and without T2D.

The influence of dietary carbohydrates and fats on weight gain is inconclusively understood. We studied the acute impact of these nutrients on the overall metabolic state utilizing the insulin:glucagon ratio (IGR).Following in vitro glucose and palmitate treatment, insulin and glucagon secretion from islets isolated from C57Bl/6J mice was measured. Our human in vivo study included 21 normoglycaemia (mean age 51.9 ± 16.5 years, BMI 23.9 ± 3.5 kg/mThe IGR measured from mouse islets was determined solely by glucose levels. The palmitate-stimulated hormone secretion was largely glucose independent in the analysed mouse islets. The acute meal tolerance test demonstrated that insulin and glucagon secretion is dependent on glycaemic status and meal composition, whereas the IGR was dependent upon meal composition. The relative reduction in IGR elicited by the fat-rich meal was more pronounced in obese individuals. This effect was blunted in T2D individuals with elevated HbA1c levels.The metabolic state in normoglycaemic individuals and T2D-diagnosed individuals is regulated by glucose. We demonstrate that consumption of a low carbohydrate diet, eliciting a catabolic state, may be beneficial for weight loss, particularly in obese individuals.

IntroductionLong COVID, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, post-exertional malaise, and cognitive dysfunction. There is currently no effective treatment, and the underlying mechanisms are unknown although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in Long COVID. This randomised placebo-controlled clinical trial will explore HBOT as a potential treatment for Long COVID. The primary objective is to evaluate if HBOT improves health related quality of life (HRQoL) for patients with Long COVID compared to placebo/sham. The main secondary objectives are to evaluate whether HBOT improves endothelial function, objective physical performance, and short term HRQoL.Methods and AnalysisA randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to Long COVID, with low HRQoL. Clinical data, HRQoL- questionnaires, blood samples, objective tests and activity meter data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over six weeks. Assessments for safety and efficacy will be performed at six, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND-36) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent Data Safety Monitoring Board.Ethics and DisseminationThe trial is approved by The Swedish National Institutional Review Board (2021-02634) and the Swedish Medical Product Agency (5.1-2020-36673). Positive, negative, and inconclusive results will be published in peer-reviewed scientific journals with open access.Trial RegistrationNCT04842448. EudraCT: 2021-000764-30Strengths and limitations of this trialStrengthsRandomised placebo-controlled, double-blind, parallel groups, clinical trial in compliance with ICH-GCPEvaluation of safety and efficacy, including objective and explanatory endpointsIndependent Data Safety Monitoring Board (DSMB)LimitationsNew syndrome with unknown mechanismsPower calculation is based on similar syndromesSelection bias as patients are enrolled from the same post-COVID clinic

Persistent and impaired inflammation impedes tissue healing and is a characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. In this study, we show that in human wound-edge keratinocytes, the expressions of microRNA (miR)-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, are upregulated during wound repair. However, their levels are lower in chronic ulcers than in acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines and cytokines by keratinocytes. Thus, miR-19a/b and miR-20a being crucial regulators of wound inflammation, the lack thereof may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.

Purpose: A few prospective trials and case series have suggested efficacy of hyperbaric oxygen therapy (HBOT) for treatment of severe COVID-19 but safety is a concern, especially for critically ill patients. We present the safety interim analysis of the randomised controlled trial COVID-19-HBO Methods: Randomised controlled, open label, clinical trial in compliance with good clinical practice to explore the safety and efficacy of HBOT for severe COVID-19 in critically ill patients with moderate acute respiratory distress syndrome (ARDS). Between June 3 2020 and May 17 2021, 31 patients with Severe COVID-19 and moderate to severe ARDS; PaO2/FiO2 Results: Adverse events (AE) were common, hypoxia was most commonly reported, there was no statistically significant difference between the groups. Numerically, serious adverse events (SAE) and barotrauma were more frequent in the control group. Numerically differences were in favor of the HBOT in PFI, NEWS but statistically not significant at day 7, and no difference was observed for the total oxygen burden and Cumulative Pulmonary oxygen Toxicity Dose (CPTD).Conclusions: HBOT appears safe as an intervention for critically ill patients with moderate to severe acute respiratory distress syndrome (ARDS) induced by COVID-19.Trial registration: NCT04327505 (March 31, 2020) and EudraCT 2020-001349-37 (April 24, 2020)

Background:Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia.Methods:The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes.Results:Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes.Conclusions:We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use.Funding:This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute’s Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.

Red blood cells (RBCs) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBCs were co-incubated with arteries and endothelial cells ex vivo and transfused in vivo to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBCs from patients with T2DM (T2DM RBC) and diabetic rodents induced endothelial dysfunction ex vivo and in vivo. miR-210 levels were lower in human T2DM RBC than in RBCs from healthy subjects (H RBC). Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in H RBC or RBCs from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in non-diabetic patients. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBCs via downregulating vascular PTP1B and oxidative stress in diabetic mice in vivo. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM.

Aims: As part of the SURE programme, SURE Denmark/Sweden aimed to study the real-world use of once-weekly (OW) semaglutide in adults with type 2 diabetes (T2D) in Denmark/Sweden. Methods: SURE Denmark/Sweden was an ∼30-week, prospective, multicentre, open-label, observational study, enrolling adults with T2D and ≥1 documented HbA1c value ≤12 weeks before initiating semaglutide at their physician's discretion. Primary (change in HbA1c) and secondary (including change in body weight, glycaemic and weight-loss target achievement) endpoints were assessed between baseline and end of study (EOS). Results: Of the 331 patients initiating semaglutide, 282 (85%) completed the study on treatment. For the latter, estimated mean changes [95% confidence interval] in HbA1c and body weight between baseline and EOS were –1.2 [–1.3; –1.1]%-points (–13 [–14; –12] mmol/mol) and –5.4 [–6.0; –4.7] kg (both p < 0.0001), respectively, with similar results in Denmark and Sweden. At EOS, 67.5% of patients achieved HbA1c

Background A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. Methods The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. Findings CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. Interpretation CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

Objective. Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the HIF-1A Pro582Ser polymorphism is more resistant to hyperglycemia-mediated repression, thus protecting against the development of diabetic nephropathy. In this study, we have investigated the effect of the HIF-1A Pro582Ser polymorphism on the development of DR and further dissected the mechanisms by which the polymorphism confers a relative resistance to the repressive effect of hyperglycemia. Research Design and Method. 703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to the HIF-1A Pro582Ser polymorphism. The effect of glucose on a stable HIF-1A construct with a Pro582Ser mutation was evaluated in vitro. Results. We identified a protective effect of HIF-1A Pro582Ser against developing severe DR with a risk reduction of 95%, even when adjusting for known risk factors for DR such as diabetes duration, hyperglycemia, and hypertension. The Pro582Ser mutation does not cancel the destabilizing effect of glucose but is followed by an increased transactivation activity even in high glucose concentrations. Conclusion. The HIF-1A genetic polymorphism has a protective effect on the development of severe DR. Moreover, the relative resistance of the HIF-1A Pro582Ser polymorphism to the repressive effect of hyperglycemia is due to the transactivation activity rather than the protein stability of HIF-1α.

BACKGROUND: The LeucoPatch device uses bedside centrifugation without additional reagents to generate a disc comprising autologous leucocytes, platelets, and fibrin, which is applied to the surface of the wound. We aimed to test the effectiveness of LeucoPatch on the healing of hard-to-heal foot ulcers in people with diabetes.METHODS: This was a multicentre, international, observer-masked, randomised controlled trial of people with diabetes and a hard-to-heal foot ulcer done in 32 specialist diabetic foot clinics in three countries (UK, Denmark, and Sweden). After a 4-week run-in period, those with a reduction in ulcer area of less than 50% were randomly allocated (1:1) by computer-generated, web-based randomisation (block sizes of two, four, and six) to either prespecified good standard care alone or care plus weekly application of LeucoPatch. The primary outcome was the proportion of ulcers that healed within 20 weeks assessed in the intention-to-treat population (all participants with post-randomisation data collected), defined as complete epithelialisation (confirmed by an observer who was masked to randomisation group), and remained healed for 4 weeks. This trial is registered with the ISRCTN registry, number 27665670, and ClinicalTrials.gov, number NCT02224742.FINDINGS: Between Aug 30, 2013, and May 3, 2017, 269 participants were randomly allocated to receive treatment (137 to receive standard care and 132 to receive LeucoPatch). The mean age was 61·9 years (SD 11·6), 217 (82%) were men, and 222 (83%) had type 2 diabetes. In the LeucoPatch group, 45 (34%) of 132 ulcers healed within 20 weeks versus 29 (22%) of 134 ulcers in the standard care group (odds ratio 1·58, 96% CI 1·04-2·40; p=0·0235) by intention-to-treat analysis. Time to healing was shorter in the LeucoPatch group (p=0·0246) than in the standard care group. No difference in adverse events was seen between the groups. The most common serious adverse event (SAE) was diabetic foot infection (24 events in the LeucoPatch group [24% of all SAEs] and 20 in the standard care group [27% of all SAEs]. There were no device-related adverse events.INTERPRETATION: The use of LeucoPatch is associated with significant enhancement of healing of hard-to-heal foot ulcers in people with diabetes.FUNDING: Reapplix ApS.

Summary Dihydroorotate dehydrogenase (DHODH) is essential for the de novo synthesis of pyrimidine ribonucleotides, and as such, its inhibitors have been long used to treat autoimmune diseases and are in clinical trials for cancer and viral infections. Interestingly, DHODH is located in the inner mitochondrial membrane and contributes to provide ubiquinol to the respiratory chain. Thus, DHODH provides the link between nucleotide metabolism and mitochondrial function. Here we show that pharmacological inhibition of DHODH reduces mitochondrial respiration, promotes glycolysis, and enhances GLUT4 translocation to the cytoplasmic membrane and that by activating tumor suppressor p53, increases the expression of GDF15, a cytokine that reduces appetite and prolongs lifespan. In addition, similar to the antidiabetic drug metformin, we observed that in db/db mice, DHODH inhibitors elevate levels of circulating GDF15 and reduce food intake. Further analysis using this model for obesity-induced diabetes revealed that DHODH inhibitors delay pancreatic β cell death and improve metabolic balance., Graphical abstract, Highlights • DHODH inhibitors impair respiration and increase glycolysis. • They promote the expression and secretion of GDF15 in a p53-dependent manner. • In hyperphagic db/db mice, DHODH inhibitors increase circulating GDF15. • They protect pancreatic β cells and improve glucose balance in these mice., Biological sciences ; Physiology ; Cellular physiology ; Endocrinology ; Diabetology

In this protocol, we describe a method to monitor cell migration by live-cell imaging of adherent cells. Scratching assay is a common method to investigate cell migration or wound healing capacity. However, achieving homogenous scratching, finding the optimal time window for end-point analysis and performing an objective image analysis imply, even for practiced and adept experimenters, a high chance for variability and limited reproducibility. Therefore, our protocol implemented the assessment for cell mobility by using homogenous wound making, sequential imaging and automated image analysis. Cells were cultured in 96-well plates, and after attachment, homogeneous linear scratches were made using the IncuCyte ( ® ) WoundMaker. The treatments were added directly to wells and images were captured every 2 hours automatically. Thereafter, the images were processed by defining a scratching mask and a cell confluence mask using a software algorithm. Data analysis was performed using the IncuCyte ( ® ) Cell Migration Analysis Software. Thus, our protocol allows a time-lapse analysis of treatment effects on cell migration in a highly reliable, reproducible and re-analyzable manner.

Wound healing is a high energy demanding process that needs a good coordination of the mitochondria with glycolysis in the characteristic highly hypoxic environment. In diabetes, hyperglycemia impairs the adaptive responses to hypoxia with profound negative effects on different cellular compartments of wound healing. miR-210 is a hypoxia-induced microRNA that regulates cellular metabolism and processes important for wound healing. Here, we show that hyperglycemia blunted the hypoxia-dependent induction of miR-210 both in vitro and in human and mouse diabetic wounds. The impaired regulation of miR-210 in diabetic wounds is pathogenic, since local miR-210 administration accelerated wound healing specifically in diabetic but not in non-diabetic mice. miR-210 reconstitution restores the metabolic balance in diabetic wounds by reducing oxygen consumption rate and ROS production and by activating glycolysis with positive consequences on cellular migration. In conclusion, miR-210 accelerates wound healing specifically in diabetes through improvement of the cellular metabolism., Narayanan et al. show that local administration of miR-210 accelerates wound healing specifically in diabetic mice. They find that miR-210 restores the metabolic balance in diabetic wounds by activating glycolysis and cellular migration. This study presents miR-210 as a potential therapeutic option to treat diabetic wound healing.

Graphical abstract Hypoxia-inducible factors (HIFs) are the key regulators of oxygen homeostasis in response to hypoxia. In diabetes, multiple tissues are hypoxic but adaptive responses to hypoxia are impaired due to insufficient activation of HIF signalling, which results from inhibition of HIF-1α stability and function due to hyperglycaemia and elevated fatty acid levels. In this review, we will summarise and discuss current findings about the regulation of HIF signalling in diabetes and the pathogenic roles of hypoxia and dysregulated HIF signalling in the development of diabetes and its complications. The therapeutic potential of targeting HIF signalling for the prevention and treatment of diabetes and related complications is also discussed. Supplementary Information The online version contains a slideset of the figures for download, available at 10.1007/s00125-021-05380-z.

There is a large unmet medical need to find disease modifying therapies against neurodegenerative diseases. This review summarizes data indicating that insulin resistance occurs in neurodegeneration and strategies to normalize insulin sensitivity in neurons may provide neuroprotective actions. In particular, recent preclinical and clinical studies in Parkinson's disease and Alzheimer's disease have indicated that glucagon-like peptide 1 (GLP1) agonism and dipeptidyl peptidase-4 inhibition may exert neuroprotection. Mechanistic insights from these studies and future directions for drug development against neurodegeneration based on GLP1 agonism are discussed.

Multiple daily insulin injections are an integral part of life for patients with type 1 diabetes (T1D). Moreover, patients’ schedules can change from day-to-day, further complicating T1D management. This study aimed to analyze daily injection patterns for patients with T1D. This post-hoc observational study included children and adults with T1D from Sweden using NovoPen® 6 with bolus insulin (primarily insulin aspart) and/or basal insulin (primarily insulin degludec). Injection data were uploaded via the Glooko® cloud system. Daily bolus and basal injections timing profiles were documented, weighting each dose relative to the total daily dose. Time difference between two consecutive basal insulin injections was used to evaluate basal timing variation. In total 159 adults and 47 children were included in the analysis, with a total of 38678 days of bolus injections and 17869 days of basal injections. The mean bolus daily injection profile displayed peaks at typical mealtimes but with substantial variation across patients and between adults and children (Figure 1). In those receiving insulin degludec timing of consecutive basal injections differed by more than 6 hr in ∼9% of the injections for adults and 7% for children. These real-world data give a unique insight into the bolus and basal adherence of pediatric and adult patients with T1D. Furthermore, the results illustrate the flexibility needed for basal injections to enable optimal management of T1D. Disclosure S. Catrina: None. N.V. Hartvig: Employee; Self; Novo Nordisk A/S. A. Kaas: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J. Moller: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. A.M. Mårdby: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J.H. Jendle: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Sanofi.

Mealtime injection of bolus insulin is critical for maintaining good glycemic control in patients with type 1 diabetes (T1D). It has previously been shown in a real-world setting that patients using connected pens had fewer missed mealtime injections of bolus doses as well as improved time-in-range (TIR) compared to baseline. This subgroup post-hoc study examined the effect of using connected pens on timing of bolus doses in adults and the relationship between timing of the insulin dose and glycemic variability. In a non-interventional study, conducted at 12 Swedish diabetes clinics, connected pens with bolus and/or basal insulin were prescribed to adults with T1D. Injection- and continuous glucose monitoring (CGM) data were collected at routine clinic visits. CGM data were also uploaded at home. These data were used by healthcare providers (HCPs) and patients during visits at the clinic. Meals were subsequently detected based on the CGM signals using the clinically validated Glucose Rate Increase Detector algorithm. A bolus dose given 60-120 minutes after the estimated start of the meal was defined as a late-bolus dose. In total 96 patients with 2238 days of acceptable CGM coverage (≥ 70%) were included in the analysis. The mean number of late-bolus doses decreased from 0.32 per day (95% CI [0.26;0.39]) at baseline to 0.18 per day [0.13;0.27] at follow-up, corresponding to a 42% reduction (p = 0.005). A significant correlation between the timing of the bolus dose and the coefficient of variation (CV) of the CGM signal was found; each 10-minute delay of the bolus dose was associated with an increase of 0.5% CV (p < 0.0001) on average. This study confirms that timely injection of bolus doses relative to meals is correlated with a more stable glycemic control. Also, the results indicate that timely bolus dosing can be a challenge in everyday life but that data from connected pens may help support patient behavior through improved interaction with HCP. Disclosure J.H. Jendle: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. N.V. Hartvig: Employee; Self; Novo Nordisk A/S. A. Kaas: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J. Moller: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. A.M. Mårdby: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. S. Catrina: None.

There is a large unmet medical need to find disease modifying therapies against neurodegenerative diseases. This review summarizes data indicating that insulin resistance occurs in neurodegeneration and strategies to normalize insulin sensitivity in neurons may provide neuroprotective actions. In particular, recent preclinical and clinical studies in Parkinson's disease and Alzheimer's disease have indicated that glucagon-like peptide 1 (GLP1) agonism and dipeptidyl peptidase-4 inhibition may exert neuroprotection. Mechanistic insights from these studies and future directions for drug development against neurodegeneration based on GLP1 agonism are discussed.

Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual ß-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.

Introduction: The prevalence of diabetes type 2 is increasing worldwide, thus the search of novel alternative therapies is needed. According to their traditional use, we selected five Bolivian plants Chenopodium quinoa (CQ) Amaranthus caudatus (AC), Chenopodium pallidicaule (CP), Lupinus mutabilis (LM) and Smallanthus sonchifolius (SS) that are traditionally used to control glycemia. Methods: The effect of a single oral administration of Ethanolic (EtOH), hydro-ethanolic (EtOH70) and aqueous (Aq) extracts from all plant species were tested for their effect on blood glucose in non-fasted mice and during the oral glucose tolerance test (OGTT). The effect on insulin secretion was evaluated in mice pancreatic islets. Results: EtOH70 extracts of all the plants showed glucose-reducing effect at the highest dose evaluated (2000 mg/ kg b.w.). EtOH70 extracts improved the glucose tolerance evaluated by the OGTT in mice fasted for 12 hours. The extracts have different effects on glucose homeostasis since just extracts of AC, LM and CQ but not CP and SS increased insulin secretion as shown on mice pancreatic islets. The phytochemical qualitative characterization of EtOH70 extracts detected phenolic acids and flavonoids in AC, CP and CQ; alkaloids in LM and anthocyanidins in SS. None of EtOH70 extracts tested showed in vitro or in vivo acute toxicity at concentrations where they exhibit glucose lowering effects. Conclusions: We report here that extracts from AC, CQ, CP, LM and SS exhibit glucose lowering effect while just AC, CQ and LM stimulate directly the insulin secretion., Introducción: La prevalencia de diabetes tipo 2 está aumentando en todo el mundo, por lo que se necesita la búsqueda de nuevas terapias alternativas. Según su uso tradicional, seleccionamos cinco plantas bolivianas Chenopodium quinoa (CQ) Amaranthus caudatus (AC), Chenopodium pallidicaule (CP), Lupinus mutabilis (LM) y Smallanthus sonchifolius (SS) que se usan tradicionalmente para controlar la glucemia. Métodos: Se evaluó el efecto de la administración oral única de extractos etanólicos (EtOH), hidroetanólicos (EtOH70) y acuosos (Aq) de las plantas mencionadas para determinar su efecto sobre la glucosa en sangre en ratones en o sin ayunas y durante la prueba de tolerancia a la glucosa oral (PTGO). El efecto sobre la secreción de insulina se evaluó en islotes pancreáticos de ratones. Resultados: Los extractos de EtOH70 de todas las plantas disminuyeron la glucemia a la dosis más alta evaluada (2000 mg / kg b.w.). Los extractos de EtOH70 mejoraron la tolerancia a la glucosa evaluada mediante la PTGO en ratones con ayuno de 12 horas. Los extractos tienen diferentes efectos sobre la homeostasis de la glucosa, ya que solo los extractos de AC, LM y CQ pero no CP y SS aumentaron la secreción de insulina como se muestra en los islotes pancreáticos de los murinos. La caracterización cualitativa fitoquímica de extractos de EtOH70 detectó ácidos fenólicos y flavonoides en AC, CP y CQ, alcaloides en LM y antocianidinas en SS. Ninguno de los extractos de EtOH70 probados mostró toxicidad aguda in vitro o in vivo a concentraciones en las que exhiben efectos reductores de glucosa. Conclusión: Los extractos de AC, CQ, CP, LM y SS exhiben un efecto reductor de la glucosa, mientras que solo AC, CQ y LM estimulan directamente la secreción de insulina., Swedish International Development Cooperation Agency, SIDA