Search

Consumption of traditional foods is decreasing amid a lifestyle transition in Greenland as incidence of type 2 diabetes (T2D) increases. In homozygous carriers of a TBC1D4 variant, conferring postprandial insulin resistance, the risk of T2D is markedly higher. We investigated the effects of traditional marine diets on glucose homoeostasis and cardio-metabolic health in Greenlandic Inuit carriers and non-carriers of the variant in a randomised crossover study consisting of two 4-week dietary interventions: Traditional (marine-based, low-carbohydrate) and Western (high in imported meats and carbohydrates). Oral glucose tolerance test (OGTT, 2-h), 14-d continuous glucose and cardio-metabolic markers were assessed to investigate the effect of diet and genotype. Compared with the Western diet, the Traditional diet reduced mean and maximum daily blood glucose by 0·17 mmol/l (95 % CI 0·05, 0·29; P = 0·006) and 0·26 mmol/l (95 % CI 0·06, 0·46; P = 0·010), respectively, with dose-dependency. Furthermore, it gave rise to a weight loss of 0·5 kg (95 % CI; 0·09, 0·90; P = 0·016) relative to the Western diet and 4 % (95 % CI 1, 9; P = 0·018) lower LDL:HDL-cholesterol, which after adjustment for weight loss appeared to be driven by HDL elevation (0·09 mmol/l (0·03, 0·15), P = 0·006). A diet-gene interaction was indicated on insulin sensitivity in the OGTT (p = 0·093), which reflected a non-significant increase of 1·4 (-0·6, 3·5) mmol/l in carrier 2-h glucose. A Traditional diet marginally improved daily glycaemic control and plasma lipid profile compared with a Westernised diet in Greenlandic Inuit. Possible adverse effects on glucose tolerance in carriers of the TBC1D4 variant warrant further studies.

Introduction: Patients with type 1 diabetes (T1D) demonstrate brain alterations, including white matter lesions and cerebral atrophy. In this case-control study, we investigated if a reason for this atrophy could be because of diabetes-related complications affecting cerebrovascular or cerebral glycolytic functions. Cerebral physiological dysfunction can lead to energy deficiencies and, consequently, neurodegeneration., Methods: We examined 33 patients with T1D [18 females, mean age: 50.8 years (range: 26-72)] and 19 matched healthy controls [7 females, mean age: 45.0 years (range: 24-64)]. Eleven (33%) of the patients had albuminuria. Total brain volume, brain parenchymal fraction, gray matter volume and white matter volume were measured by anatomical MRI. Cerebral vascular and glycolytic functions were investigated by measuring global cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO 2 ) and cerebral lactate concentration in response to the inhalation of hypoxic air (12-14% fractional oxygen) using phase-contrast MRI and magnetic resonance spectroscopy (MRS) techniques. The inspiration of hypoxic air challenges both cerebrovascular and cerebral glycolytic physiology, and an impaired response will reveal a physiologic dysfunction., Results: Patients with T1D and albuminuria had lower total brain volume, brain parenchymal fraction, and gray matter volume than healthy controls and patients without albuminuria. The inhalation of hypoxic air increased CBF and lactate in all groups. Patients with albuminuria had a significantly ( p  = 0.032) lower lactate response compared to healthy controls. The CBF response was lower in patients with albuminuria compared to healthy controls, however not significantly ( p  = 0.24) different. CMRO 2 was unaffected by the hypoxic challenge in all groups ( p  > 0.16). A low lactate response was associated with brain atrophy, characterized by reduced total brain volume ( p  = 0.003) and reduced gray matter volume ( p  = 0.013)., Discussion: We observed a reduced response of the lactate concentration as an indication of impaired glycolytic activity, which correlated with brain atrophy. Inadequacies in upregulating cerebral glycolytic activity, perhaps from reduced glucose transporters in the brain or hypoxia-inducible factor 1 pathway dysfunction, could be a complication in diabetes contributing to the development of neurodegeneration and declining brain health., Competing Interests: JL reports having given lectures for Boehringer Ingelheim (all fees given to Steno Diabetes Center Copenhagen). NH reports full-time employee status in Novo Nordisk A/S from March 1st 2023 and stock ownership in Novo Nordisk A/S and Akcea Therapeutics Inc. PR has received grants for research from Astra Zeneca, Bayer and Novo Nordisk (outside this project) and has received honoraria (to Steno Diabetes Center Copenhagen) from Astra Zeneca, Abbott, Novo Nordisk, Bayer, Boehringer Ingelheim, Merck, Sanofi Aventis, and Eli Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vestergaard, Laursen, Heinrich, Rossing, Hansen and Larsson.)

Background: Low baroreflex sensitivity is an indicator of early cardiovascular autonomic neuropathy. We explored the association between baroreflex sensivity and blood oxygen saturation (SpO 2 ) in type 1 diabetes and various degrees of microvascular disease., Methods: In this Danish-Finnish cross-sectional multicentre study, baroreflex sensivity and SpO 2 (pulse oximetry) were examined in persons with type 1 diabetes and normoalbuminuria (n = 98), microalbuminuria (n = 28), or macroalbuminuria (n = 43), and in non-diabetic controls (n = 54). Associations and differences between groups were analysed using regression models and adjustment included age, sex, smoking, HbA 1c , blood haemoglobin, urine albumin creatinine ratio, body mass index, and estimated glomerular filtration rate., Results: In type 1 diabetes, higher baroreflex sensitivity was associated with higher SpO 2 before adjustment (% increase per one % increase in SpO 2  = 20 % (95%CI: 11-30); p < 0.001) and the association remained significant after adjustment (p = 0.02). Baroreflex sensitivity was not different between non-diabetic controls and persons with type 1 diabetes and normoalbuminuria (p = 0.052). Compared with type 1 diabetes and normoalbuminuria, baroreflex sensitivity was lower in micro- (p < 0.001) and macroalbuminuria (p < 0.001). SpO 2 was lower in persons with type 1 diabetes and normoalbuminuria compared with non-diabetic controls (p < 0.01). Within the participants with type 1 diabetes, SpO 2 was not different in micro- or macroalbuminuria compared with normoalbuminuria (p-values > 0.05), but lower in macro-compared with microalbuminuria (p < 0.01)., Conclusions: Lower baroreflex sensitivity was associated with lower SpO 2 in type 1 diabetes. The present study support the hypothesis that hypoxia could be a therapeutic target in persons with type 1 diabetes., Competing Interests: Declaration of competing interest J.C.L. reports having given a lecture for Boehringer Ingelheim, the fee was given to Steno Diabetes Center Copenhagen. P.R. reports having received research grants from Astra Zeneca and Novo Nordisk and given lectures for Astra Zeneca, Mundipharma and Boehringer Ingelheim and has served as a consultant for Astra Zeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Astellas, Gilead, Sanofi Aventis Vifor, and Novo Nordisk, all fees given to Steno Diabetes Center. P-H.G. has received lecture honoraria from Astellas, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Medscape, MSD, Mundipharma, Novartis, Novo Nordisk, PeerVoice, Sanofi and Sciarc, and is an advisory board member of AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Medscape, MSD, Mundipharma, Novo Nordisk and Sanofi. C.S.H. has received lecture honoraria to Steno Diabetes Center Copenhagen from Novo Nordisk. M.F-M. reports having received research grants from Novo Nordisk and speaking fees from Boehringer Ingelheim, Novartis, Baxter and Sanofi. M.B., T.W.H. and L.B. have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: COVID-19 is associated with subclinical myocardial injury. Exogenous ketone esters acutely improve left myocardial function in healthy participants and patients with heart failure, but the effects have not been investigated in participants previously hospitalized for COVID-19., Methods: This is a randomized placebo-controlled double-blind crossover study comparing a single oral ketone ester dose of 395 mg/kg with placebo. Fasting participants were randomized to either placebo in the morning and oral ketone ester in the afternoon or vice versa. Echocardiography was performed immediately after intake of the corresponding treatment. Primary outcome was left ventricular ejection fraction (LVEF). Secondary outcomes were absolute global longitudinal strain (GLS), cardiac output and blood oxygen saturation. Linear mixed effects models were used to assess differences., Results: We included 12 participants previously hospitalized for COVID-19 with a mean (±SD) age of 60 ± 10 years. The mean time from hospitalization was 18 ± 5 months. Oral ketone esters did not increase LVEF between placebo and oral ketone ester [mean difference: -0.7% (95% CI -4.0 to 2.6%), p = 0.66], but increased GLS [1.9% (95% CI: 0.1 to 3.6%), p = 0.04] and cardiac output [1.2 L/min (95% CI: -0.1 to 2.4 L/min), p = 0.07], although non-significant. The differences in GLS remained significant after adjustment for change in heart rate ( p = 0.01). There was no difference in blood oxygen saturation. Oral ketone esters increased blood ketones over time (peak level 3.1 ± 4.9 mmol/L, p < 0.01). Ketone esters increased blood insulin, c-peptide, and creatinine, and decreased glucose and FFA (all p ≤ 0.01) but did not affect glucagon, pro-BNP, or troponin I levels (all p > 0.05)., Conclusion: In patients previously hospitalized with COVID-19, a single oral dose of ketone ester had no effect on LVEF, cardiac output or blood oxygen saturation, but increased GLS acutely., Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04377035., Competing Interests: FD reports having served as a consultant for Bayer. TB-S reports serving as steering committee member of the Amgen financed GALACTIC-HF trial, chief investigator and steering committee chair of the Sanofi Pasteur financed “NUDGE-FLU” trial, chief investigator and steering committee chair of the Sanofi Pasteur financed “DANFLU-1” trial, chief investigator and steering committee chair of the Sanofi Pasteur financed “DANFLU-2” trial, steering committee member of “LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System” trial. Being on the advisory board for Sanofi Pasteur, Amgen, and GSK. Receiving speaker honorarium from Bayer, Novartis, Sanofi Pasteur, and GSK and research grants from GE HealthCare and Sanofi Pasteur. PR reports having received research grants from AstraZeneca and Novo Nordisk and given lectures for AstraZeneca, Mundipharma, and Boehringer Ingelheim and has served as a consultant for AstraZeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Astellas, Gilead, Sanofi Aventis Vifor, and Novo Nordisk, all fees given to Steno Diabetes Center Copenhagen. JL reports receiving a speaker honorarium from Boehringer Ingelheim, all fees given to Steno Diabetes Centre Copenhagen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wodschow, Davidovski, Christensen, Lassen, Skaarup, Nygaard, Møller, Rungby, Biering-Sørensen, Rossing, Jensen and Laursen.)

Aims: To assess cardiac angiogenesis in type 2 diabetes by positron emission tomography (PET) tracer [ 68 Ga]Ga-NODAGA-E[(cRGDyK)] 2 ( 68 Ga-RGD) imaging., Methods: Cross-sectional study including 20 persons with type 2 diabetes and 10 non-diabetic controls (CONs). Primary prespecified outcome was difference in cardiac angiogenesis (cardiac 68 Ga-RGD mean target-to-background ratio [TBR mean ]) between type 2 diabetes and CONs. Secondary outcome was to investigate associations between cardiac angiogenesis and kidney function and other risk factors., Results: Participants with type 2 diabetes had a mean ± SD age of 61 ± 9 years, 30% were women, median (IQR) diabetes duration of 11 (6-19) years and 3 (15%) had a history of cardiovascular disease. The CONs had comparable age and sex distribution to the participants with type 2 diabetes, and none had a history of coronary artery disease. Myocardial flow reserve was lower in type 2 diabetes (2.7 ± 0.6) compared with CONs (3.4 ± 1.2) ( p  = 0.03) and coronary artery calcium score was higher (562 [142-905] vs. 1 [0-150] p  = 0.04). Cardiac 68 Ga-RGD TBR mean was similar in participants with type 2 diabetes (0.89 ± 0.09) and CONs (0.89 ± 0.10) ( p  = 0.92). Cardiac 68 Ga-RGD TBR mean was not associated with estimated glomerular filtration rate, urine albumin creatinine ratio, cardiovascular disease, coronary artery calcium score or baroreflex sensitivity, neither in pooled analyses nor in type 2 diabetes., Conclusions: Cardiac angiogenesis, evaluated with 68 Ga-RGD PET, was similar in type 2 diabetes and CONs. Cardiac angiogenesis was not associated with kidney function or other risk markers in pooled analyses or in analyses restricted to type 2 diabetes., (© 2022 Diabetes UK.)

Changes in cellular bioenergetics such as mitochondrial respiration and glycolysis may play a role in the pathogenesis of various diseases including type 1 diabetes (T1D). We used Seahorse extracellular flux technology to analyse the efficiency of glycolysis and mitochondrial oxidative phosphorylation in peripheral blood mononuclear cells (PBMCs) obtained from fresh blood samples from fifteen long-term T1D individuals with albuminuria (five females) with an average (±SD) age of 58 (±14) years and 15 age and sex-matched healthy non-diabetic controls. In T1D PBMCs, mitochondrial proton leak was higher (T1D: 21,3 ± 1,46 pmol/min; controls: 17,3 ± 1,24 pmol/min; p = 0,049) and glucose (5 mM) suppressed mitochondrial proton leak more than in healthy controls. Further, PBMCs from T1D individuals had higher glycolysis compared with healthy controls (T1D: 9,68 ± 0,94 mpH/min; controls: 7,07 ± 0,64 mpH/min; p = 0,032). Correlation analysis of circulating inflammatory factors identified Leukaemia Inhibitor factor 1 (LIF) being negatively correlated with PBMC glycolysis. Our results suggest that mitochondrial and glycolytic pathways of PBMCs from long-term T1D individuals with albuminuria might be dysfunctional, possibly due to increased cellular metabolic load and/or oxidative stress in which inflammatory factors could play a role., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Context: Blood oxygen saturation (SpO2) is lower in type 1 diabetes (T1D) compared with nondiabetic controls. Hypoxia (low tissue oxygenation) is thought to be a risk factor for progression of diabetic complications, but it is unknown whether hypoxemia (low SpO2) is associated with diabetic complications., Objective: To test if hypoxemia is associated with presence of diabetic complications in T1D., Design, Setting, and Methods: Cross-sectional study in persons with T1D divided by a previously suggested threshold in low (<96%) and high (≥96%) SpO2, measured in the supine position with pulse oximetry. Complications included albuminuria (2 of 3 consecutive measurements ≥30 mg/g), any diabetic retinopathy, neuropathy, and history of cardiovascular disease (CVD). Odds ratios were adjusted for age, diabetes duration, sex, smoking, physical activity, body mass index, systolic blood pressure, and blood hemoglobin., Results: We included 659 persons, 23 (3.5%) with low and 636 (96.5%) with high SpO2. In total, 151 (23%) had albuminuria, 233 (36%) had retinopathy, 231 (35%) had neuropathy, and 72 (11%) had CVD. The adjusted odds ratio (95% CI, P value) for low vs high SpO2 was 3.4 (1.3-8.7, P = 0.01) for albuminuria, 2.8 (1.0-7.5, P = 0.04) for retinopathy, 5.8 (1.8-18.6, P < 0.01) for neuropathy, and nonsignificant for CVD (0.6 [0.2-2.4, P = 0.51])., Conclusions: SpO2 below 96% was associated with increased presence of albuminuria, retinopathy, and neuropathy in T1D, but not with CVD. Whether hypoxemia could be a target of intervention to prevent progression in microvascular disease in type 1 diabetes should be investigated., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Low blood oxygen saturation is associated with increased mortality and persons with diabetes have sub-clinical hypoxemia. We aimed to confirm the presence of sub-clinical hypoxemia in pre-diabetes, screen-detected diabetes and known diabetes., Methods: Pre-diabetes was defined as hemoglobin A1C (HbA 1C ) ≥ 42 mmol/mol and <48 mmol/mol; known diabetes as history or treatment of diabetes; screen-detected diabetes as no history or treatment of diabetes and HbA 1C ≥ 48 mmol/mol. Blood oxygen saturation was measured with pulse oximetry. Urine albumin-to creatinine ratio (UACR) was measured on a single spot urine., Results: The study included 829 adults (≥18 years) with diabetes (713 (86%) with known diabetes; 116 (14%) with screen-detected diabetes) and 12,747 without diabetes (11,981 (94%) healthy controls; 766 (6%) with pre-diabetes). Mean (95% CI) blood oxygen saturation was 96.3% (96.3% to 96.4%) in diabetes which was lower than in non-diabetes [97.3% (97.2-97.3%)] after adjustment for age, gender, and smoking ( p < 0.001), but significance was lost after adjustment for BMI ( p = 0.25). Sub-groups with pre-diabetes and screen-detected diabetes had lower blood oxygen saturations than healthy controls ( p -values < 0.01). Lower blood oxygen saturation was associated with higher UACR., Conclusions: Persons with pre-diabetes and screen-detected diabetes have sub-clinical hypoxemia, which is associated with albuminuria., Competing Interests: Author JL reports having received a speaking fee from Boehringer Ingelheim, which was given to Steno Diabetes Center Copenhagen. Author PR reports having received research grants from Astra Zeneca and Novo Nordisk and given lectures for Astra Zeneca, and Boehringer Ingelheim and has served as a consultant for Astra Zeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Astellas, Gilead, Sanofi Aventis Vifor, and Novo Nordisk, all fees given to Steno Diabetes Center Copenhagen. Author MF-M reports having received research grants from Novo Nordisk and speaking fees from Boehringer Ingelheim, Novartis, Baxter and Sanofi. Author MJ has received research grants from Astra Zeneca, AMGEN, Boehringer Ingelheim, Novo Nordisk, and Sanofi Aventis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Laursen, Jepsen, Bruun-Rasmussen, Frimodt-Møller, Jørgensen, Rossing and Hansen.)

Objective: We investigated the association between the cardiovascular autonomic neuropathy (CAN) diagnosis and glucose variability (GV) in type 1 diabetes (T1D), as autonomic dysfunction previously has been associated with increased GV., Research Design and Methods: CAN was assessed by three recommended cardiovascular reflex tests (CARTs). Glucose metrics were obtained from 10-day blinded continuous glucose monitoring (CGM). Between-group differences in GV indices were assessed by regression analyses in 24 participants with T1D with CAN and 24 matched control subjects without CAN., Results: The CAN diagnosis was associated with 4.9% (95% CI 1.0, 8.7) higher coefficient of variation (CV) (P = 0.014), 0.7 mmol/L (0.3, 1.1) higher SD (P = 0.002) of glucose, and 1.4 mmol/mol (0.0, 2.7) higher mean amplitude of glycemic excursions (P = 0.047). Lower measures of CARTs were associated with higher CV, SD, and time above range values., Conclusions: The CAN diagnosis associates with a significantly higher GV in T1D, despite a high prevalence of routine CGM use., (© 2022 by the American Diabetes Association.)

Background: We used magnetic resonance imaging (MRI) to study kidney energetics in persons with and without type 1 diabetes (T1D)., Methods: In a cross-sectional study, 15 persons with T1D and albuminuria and 15 non-diabetic controls (CONs) underwent multiparametric MRI (3 Tesla Philips Scanner) to quantify renal cortical and medullary oxygenation (R 2 *, higher values correspond to higher deoxyhaemoglobin concentration), renal perfusion (arterial spin labelling) and renal artery blood flow (phase contrast). Analyses were adjusted for age, sex, systolic blood pressure, plasma haemoglobin, body mass index and estimated glomerular filtration rate (eGFR)., Results: Participants with T1D had a higher median (Q1; Q3) urine albumin creatinine ratio (UACR) than CONs [46 (21; 58) versus 4 (3; 6) mg/g; P  < .0001] and a lower mean ± SD eGFR (73 ± 32 mL/min/1.73 m 2  versus 88 ± 15 mL/min/1.73 m 2 ;   P  = .12), although not significantly. Mean medullary R 2 * was lower in T1D (34 ± 6/s versus 38 ± 5/s; P  < .01) corresponding to a higher oxygenation. R 2 * was not different in the cortex. Cortical perfusion was lower in T1D (163 ± 40 versus 224 ± 49 mL/100 g/min; P  < .001). Renal artery blood flow was lower in T1D than in CONs (360 ± 130 versus 430 ± 113 mL/min; P  = .05). In T1D, lower cortical oxygenation and renal artery blood flow were both associated with higher UACR and lower eGFR ( P  < .05)., Conclusions: Participants with T1D and albuminuria exhibited higher medullary oxygenation than CONs, despite lower cortical perfusion and renal artery blood flow. This might reflect perturbed kidney energetics leading to a higher setpoint of medullary oxygenation in T1D. Lower cortical oxygenation and renal artery blood flow were associated with higher UACR and lower eGFR in T1D., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Elevated soluble urokinase plasminogen activator receptor (suPAR) is highly associated with increased risk of diabetic complications. Dapagliflozin is a drug inhibiting the sodium-glucose co-transporter 2 in the kidney to decrease blood glucose, while also decreasing risk of kidney disease, heart failure, and death. Therefore, we have investigated suPAR as a monitor for treatment effect with dapagliflozin in diabetes. Methods: suPAR was measured in two double-blinded randomized clinical cross-over trials. The first trial investigated the effect of a single dose dapagliflozin 50 mg or placebo 12 h after intake, in individuals with type 1 diabetes and albuminuria. The second trial investigated the effect of a daily dose dapagliflozin 10 mg or placebo for 12 weeks, in individuals with type 2 diabetes and albuminuria. suPAR was measured in serum samples taken, in the acute trial, after treatment with dapagliflozin and placebo, and in the long-term trial, before and after treatment with dapagliflozin and placebo. Effect of dapagliflozin on suPAR levels were assessed using paired t -test. Results: 15 participants completed the acute trial and 35 completed the long-term trial. Mean difference in suPAR between dapagliflozin and placebo in the acute trial after 12 h was 0.70 ng/ml (95% CI: 0.66; 1.33, p = 0.49). In the long-term trial the mean difference was 0.06 ng/ml (95% CI -0.15; 0.27, p = 0.57). Conclusion: Based on our findings we conclude that suPAR is not a feasible marker to monitor the effect of treatment with dapagliflozin. Thus, a further search of suitable markers must continue., Competing Interests: T.W.H. reports having equity interest in Novo Nordisk. J.E.O is CSO, cofounder and shareholder in ViroGates, and is named inventor on patents on suPAR, owned by Copenhagen University Hospital Hvidovre, Denmark. F.P. reports having received research grants from AstraZeneca, Novo Nordisk and Novartis and lecture fees from Novartis, Eli Lilly, MSD, AstraZeneca, Sanofi, Novo Nordiskand Boehringer Ingelheim and having served as a consultant for Astra Zeneca, Bayer, Amgen, Novo Nordisk and MSD. P.R. reports giving lectures for AstraZeneca, Bayer, Novo Nordisk, Merck, and Boehringer Ingelheim; serving as a consultant for AbbVie, AstraZeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Astellas, Gilead, Mundipharma, and Novo Nordisk, with all fees given to Steno Diabetes Center Copenhagen; and having equity interest in Novo Nordisk. All other authors report no competing interests. There is no external funding to declare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rotbain Curovic, Houlind, Hansen, Eugen-Olsen, Laursen, Eickhoff, Persson and Rossing.)

Background: The mechanisms linking cardiovascular autonomic neuropathy, diabetic kidney disease and cardiovascular mortality in type 2 diabetes are widely unknown. We investigated the relationship between baseline cardiovascular autonomic function and changes in kidney and myocardial function over six years in patients with type 2 diabetes and healthy controls., Methods: Post-hoc analysis of a cohort study in 24 patients with type 2 diabetes and 18 healthy controls. Baseline determinants were cardiovascular autonomic reflex tests (heart rate response to: standing (30:15); deep breathing (E:I); and the Valsalva test) and time- and frequency-domain heart rate variability indices. Outcomes were changes in estimated glomerular filtration rate (eGFR), albuminuria, myocardial flow reserve (MFR) measured by cardiac 82 Rb Positron emission tomography computed tomography (PET/CT), and coronary artery calcium score (CACS)., Results: Mean age at inclusion was 61 ± 10 years and 36% were female. Mean follow up time was 6 ± 0 years. A lower response in heart rate to the Valsalva test (corresponding to weaker autonomic function) was associated with a larger decline in eGFR (p=0.04), but not significantly after adjustment for sex, baseline age, smoking status, systolic blood pressure, heart rate, HbA 1c , body mass index and baseline eGFR (p=0.12). A higher baseline response in heart rate to standing (30:15) was associated with a larger decline in myocardial flow reserve in the unadjusted analysis (p=0.02) and after adjustment (p=0.02). A higher response in heart rate to the Valsalva maneuver was associated with a larger increase in CACS (p = 0.02), but the association became insignificant after adjustment (p = 0.16)., Conclusion: A lower response in heart rate to the Valsalva test was associated with a larger decline in kidney function, indicating that autonomic dysfunction may predict future loss of kidney function. However, we did not find any association between lower values in cardiovascular autonomic function at baseline and a worsening in albuminuria, myocardial function, or atherosclerotic burden., Competing Interests: PR reports having received research grants from Astra Zeneca and Novo Nordisk and given lectures for Astra Zeneca, Mundipharma and Boehringer Ingelheim and has served as a consultant for Astra Zeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Astellas, Gilead, Sanofi Aventis Vifor, and Novo Nordisk, all fees given to Steno Diabetes Center. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Laursen, Rasmussen, Zobel, Hasbak, von Scholten, Holmvang, Ripa, Hansen, Frimodt-Moeller, Kjaer, Rossing and Hansen.)

Introduction: Diabetes is increasing among Greenlandic Inuit; however, the prevalence of cardiovascular autonomic neuropathy (CAN) is yet unknown. The assessment of CAN requires an ability to differentiate between normal and abnormal. The aim was to establish normative reference data of cardiovascular autonomic function in Greenlandic Inuit., Research Design and Methods: In this cross-sectional study, cardiovascular autonomic function was evaluated in participants without diabetes during the Greenlandic Population Study 2018 and in the town Qasigiannguit in 2020. Assessment included cardiovascular autonomic reflex tests (CARTs) and power spectral analysis of heart rate variability (HRV). Normative reference limits were estimated by applying piecewise linear quantile regression models at the fifth percentile. Models were adjusted for age and sex., Results: Based on examinations of 472 participants (61.7% females), normative reference data was established for all outcomes. Mean age was 54 years (SD 13.1). Higher age was inversely associated with all outcomes of CARTs and HRV. A linear fall in cardiovascular autonomic function tended to level off beyond age of 60 or 70 years for supine-to-upright position ratio and low frequency power. However, the number of observations in subjects older than 60 or 70 years was limited, which may have caused a flattening of the curve around that age. No other associations were found., Conclusions: The general level of the CARTs and HRV for all age groups is notably lower than in previous studies from other nationalities. We speculate that sociodemographic and cultural aspects of the Greenlandic Inuit population including body mass index, smoking, physical activity and alcohol consumption may have affected the cardiovascular autonomic function., Competing Interests: Competing interests: JF holds stocks in Medicus Engineering. MEJ has received research grants from Astra Zeneca, AMGEN, Sanofi Aventis and Boehringer Ingelheim. MEJ holds shares in Novo Nordisk A/S. No other potential conflicts of interest relevant to this article were reported., (© 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.)

Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria., Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R 2 * (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three- and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019-004,557-92), on ClinicalTrials.gov (NCT04193566), and is completed., Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21-58] mg/g and an eGFR of 73 (32) ml/min/1·73m 2 . The mean changes in renal cortical R 2 * from baseline to six hours were for dapagliflozin -1·1 (SD 0·7) s -1 and for placebo +1·3 (0·7) s -1 , resulting in a difference between interventions of -2·3 s -1 [95% CI -4·0 to -0·6]; p  = 0·012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events., Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R 2 * without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well., Competing Interests: P.R. has received honoraria to Steno Diabetes center Copenhagen for consultancy from AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, Vifor, and research support from Astra Zeneca and Novo Nordisk. P-H.G. has received lecture honoraria from Astellas, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Medscape, MSD, Mundipharma, Novartis, Novo Nordisk, PeerVoice, Sanofi and Sciarc, and is an advisory board member of AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Medscape, MSD, Mundipharma, Novo Nordisk and Sanofi. N.S-H. reports having stock equity in Novo Nordisk A/S and Akcea Therapeutics Inc. C.S.H. has received lecture honoraria to Steno Diabetes center Copenhagen from Novo Nordisk. J.C.L., J.M.L.M., B.H., I.K.B.R., F.S., J.S., H.B.W.L., M.F-M., and U.B.A. declare no competing interests., (© 2021 The Author(s).)

Background: Cardiac Rubidium-82 ( 82 Rb) positron emission tomography/computed tomography (PET/CT) provides a measure of the myocardial blood flow and the myocardial flow reserve, which reflects the function of both large epicardial arteries and the myocardial microcirculation. Knowledge on changes in the myocardial microvascular function over time is lacking., Methods: In this cohort study, we recruited 60 persons with type 2 diabetes and 30 non-diabetic controls, in 2013; all free of overt cardiovascular disease. All underwent a cardiac 82 Rb PET/CT scan. In 2019, all survivors (n = 82) were invited for a repeated cardiac 82 Rb PET/CT scan using the same protocol, and 29 with type 2 diabetes and 19 controls participated., Results: Median duration between visits was 6.2 years (IQR: 6.1-6.3). In the total cohort, the mean age was 66.4 years (SD: 9.3) and 33% were females. The myocardial flow reserve was lower in persons with type 2 diabetes compared to controls (p = 0.002) but there was no temporal change in the myocardial flow reserve in participants with type 2 diabetes: mean change: -0.22 (95% CI: -0.47 to 0.02) nor in controls: -0.12 (-0.49 to 0.25) or when comparing type 2 diabetes to controls: mean difference: -0.10 (95% CI: -0.52 to 0.31). The temporal reduction in stress-induced myocardial blood flow did not differ within the groups but was more pronounced in type 2 diabetes compared to controls: mean difference: -0.30 (95% CI: -0.55 to -0.04)., Conclusion: The myocardial microvascular function was impaired in persons with type 2 diabetes compared to controls but did not change significantly in either of the groups when evaluated over 6 years., (© 2021 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Introduction: Blood oxygen saturation is low compared with healthy controls (CONs) in the supine body position in individuals with type 1 diabetes (T1D) and has been associated with complications. Since most of daily life occurs in the upright position, it is of interest if this also applies in the standing body position. In addition, tissue oxygenation in other anatomical sites could show different patterns in T1D. Therefore, we investigated blood, arm and forehead oxygen levels in the supine and standing body positions in individuals with T1D (n=129) and CONs (n=55)., Research Design and Methods: Blood oxygen saturation was measured with pulse oximetry. Arm and forehead mixed tissue oxygen levels were measured with near-infrared spectroscopy sensors applied on the skin., Results: Data are presented as least squares means±SEM and differences (95% CIs). Overall blood oxygen saturation was lower in T1D (CON: 97.6%±0.2%; T1D: 97.0%±0.1%; difference: -0.5% (95% CI -0.9% to -0.0%); p=0.034). In all participants, blood oxygen saturation increased after standing up (supine: 97.1%±0.1%; standing: 97.6%±0.2%; difference: +0.6% (95% CI 0.4% to 0.8%); p<0.001). However, the increase was smaller in T1D compared with CON (CON supine: 97.3%±0.2%; CON standing: 98.0%±0.2%; T1D supine: 96.9%±0.2%; T1D standing: 97.2%±0.1%; difference between groups in the change: -0.4% (95% CI -0.6% to -0.2%); p<0.001). Arm oxygen saturation decreased in both groups after standing and more in those with T1D. Forehead oxygen saturation decreased in both groups after standing and there were no differences between the changes when comparing the groups., Conclusion: Compared with CON, individuals with T1D exhibit possible detrimental patterns of tissue oxygen adaptation to standing, with preserved adaptation of forehead oxygenation. Further studies are needed to explore the consequences of these differences., Competing Interests: Competing interests: PR has received honoraria to Steno Diabetes Center Copenhagen for consultancy from AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, Vifor, and research support from Astra Zeneca and Novo Nordisk. P-HG has received lecture honoraria from Astellas, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Medscape, MSD, Mundipharma, Novartis, Novo Nordisk, PeerVoice, Sanofi and Sciarc, and is an advisory board member of AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Medscape, MSD, Mundipharma, Novo Nordisk and Sanofi., (© 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.)

Aim: Acute oxygen inhalation and slow deep breathing improve measures of autonomic function transiently in individuals with short-duration type 1 diabetes. Our aims were to examine these interventions and changes in autonomic function in individuals with long-duration type 1 diabetes and to explore interactions with the presence of macroalbuminuria or existing cardiovascular autonomic neuropathy., Methods: Individuals with type 1 diabetes (n = 54) were exposed to acute oxygen inhalation, slow deep breathing and a combination of both (hereafter 'the combination'). Primary outcomes were change in baroreflex sensitivity and heart rate variability. Associations between changes in outcomes were evaluated using mixed effects models., Results: Mean age ± sd was 60 ± 10 years and diabetes duration was 38 ± 14 years. Changes are presented as per cent difference from baseline with 95% confidence intervals. Acute oxygen inhalation, slow deep breathing and the combination increased baroreflex sensitivity by 21 (10, 34)%, 32 (13, 53)% and 30 (10, 54)%, respectively. Acute oxygen inhalation trended towards increasing heart rate variability 8 (-1, 17)% (P = 0.056), and slow deep breathing and the combination increased heart rate variability by 33 (18, 49)% and 44 (27, 64)% respectively. Macroalbuminuria or cardiovascular autonomic neuropathy did not modify results., Conclusion: Autonomic function is improved transiently in individuals with long-duration type 1 diabetes and normoalbuminuria or macroalbuminuria by acute oxygen inhalation and slow deep breathing. There is a risk of survival bias. Autonomic dysfunction might be a reversible condition, and hypoxia might represent a target of intervention., (© 2020 Diabetes UK.)

In recent works on the Enlightenment and the origin of modern Western thought, there is often a dichotomy between Moderate versus Radical Enlightenment. This essay evaluates the early experiences of freedom of print in Sweden and Denmark against the backdrop of such assertions. Sweden and Denmark were widely diverging polities but they obtained officially recognized freedom of the press at almost the same time. The conclusion is that by the second half of the eighteenth century, the Enlightenment, whether "Radical" or "Moderate," had created a universal paradigm shift.

Context/objective: Previous studies have demonstrated that various subtypes of the metabotropic glutamate receptors (mGluRs) are expressed in the dorsal root ganglion (DRG) of the peripheral nervous system (PNS), implicating that glutamate potentially contributes to sensory transmission through these receptors. While mGluR expression has been investigated largely in the DRG, the present study focused on mGluR expression on neurons and satellite glial cells (SGCs) of the trigeminal ganglion (TG)., Materials and Methods: To address the presence of mGluRs in rat TG neurons and their corresponding SGCs, the trigeminal ganglia from six adult male Wistar rats were isolated and immunohistochemistry and immunocytochemistry were performed. The expression of mGluR1α-, mGluR2/3- and mGluR8 on TG neurons and SGCs was investigated in tissue slices and isolated cells., Results: 35.1 ± 6.0% of the TG neurons were positive for mGluR1α, whereas 39.9 ± 7.7% and 55.5 ± 6.3% were positive for mGluR2/3 and mGluR8, respectively. Immunoreactive neurons expressing mGluRs were mainly medium- to large sized, with a smaller population of small-sized neurons showing immunoreactivity. The SGCs showed immunoreactivity toward mGluR1α and mGluR8, but not mGluR2/3, both in the tissue and in isolated cells., Conclusions: Findings from the present study showed that trigeminal neurons express mGluR1α, mGluR2/3 and mGluR8, while SGCs only express mGluR1α and mGluR8. This novel evidence may advance investigations on a possible role of mGluRs in relation to trigeminal pain transmission within the craniofacial region.

Aim: The aim of this article is to investigate whether the nitric oxide (NO) donator diethylenetriamine/nitric oxide (DETA/NO) affects trigeminal sensory processing through the trigeminal ganglion in part by activating trigeminal satellite glial cells (SGCs) and whether this effect is attenuated by the anti-inflammatory compound palmitoylethanolamide (PEA)., Methods: DETA/NO was administered to isolated rat trigeminal SGCs in vitro, and injected into the rat trigeminal ganglion in vivo, in the presence or absence of PEA., Results: Administration of DETA/NO (1000 µM) increased the release of prostaglandin E 2 by SGCs. PEA (1 and 10 µM) significantly attenuated prostaglandin E 2 release. Two intraganglionic injections of DETA/NO (10 mM, 3 µl) or prostaglandin E 2 at a 30-minute interval did not evoke discharge in trigeminal ganglion neurons that innervate the rat jaw-closer muscles, but did reduce the mechanical activation threshold of their peripheral endings by 30%-50%. Intravenous administration of PEA (1 mg/kg) or ketorolac (0.5 mg/kg) prevented DETA/NO-induced afferent mechanical sensitization., Conclusions: Elevation of NO in the trigeminal ganglion results in the sensitization of the peripheral endings of masticatory muscle nociceptors to mechanical stimulation through a mechanism that involves prostaglandin E 2 release from SGCs. Attenuation of this sensitization by PEA suggests a possible option for acute management of craniofacial pain and headache., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

In the trigeminal ganglion (TG), satellite glial cells (SGCs) form a functional unit with neurons. It has been proposed that SGCs participate in regulating extracellular glutamate levels and that dysfunction of this SGC capacity can impact nociceptive transmission in craniofacial pain conditions. This study investigated whether SGCs release glutamate and whether elevation of TG glutamate concentration alters response properties of trigeminal afferent fibers. Immunohistochemistry was used to assess glutamate content and the expression of excitatory amino acid transporter (EAAT)1 and EAAT2 in TG sections. SGCs contained glutamate and expressed EAAT1 and EAAT2. Potassium chloride (10 mM) was used to evoke glutamate release from cultured rat SGCs treated with the EAAT1/2 inhibitor (3S)-3-[[3-[[4-(trifluoromethyl)ben zoyl]amino]phenyl]methoxy]-L-aspartic acid (TFB-TBOA) or control. Treatment with TFB-TBOA (1 and 10 μM) significantly reduced the glutamate concentration from 10.6 ± 1.1 to 5.8 ± 1.4 μM and 3.0 ± 0.8 μM, respectively (p<0.05). Electrophysiology experiments were conducted in anaesthetized rats to determine the effect of intraganglionic injections of glutamate on the response properties of ganglion neurons that innervated either the temporalis or masseter muscle. Intraganglionic injection of glutamate (500 mM, 3 μl) evoked afferent discharge and significantly reduced muscle afferent mechanical threshold. Glutamate-evoked discharge was attenuated bythe N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovalerate (APV) and increased by TFB-TBOA, whereas mechanical sensitization was only sensitive to APV. Antidromic invasion of muscle afferent fibers by electrical stimulation of the caudal brainstem (10 Hz) or local anesthesia of the brainstem with lidocaine did not alter glutamate-induced mechanical sensitization. These findings provide a novel mechanism whereby dysfunctional trigeminal SGCs could contribute to cranial muscle tenderness in craniofacial pain conditions such as migraine headache., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Nitric oxide (NO) is suggested to play an important role in primary headaches. It has been proposed that release of NO from satellite glial cells (SGCs) of the trigeminal ganglion (TG) could contribute to the pathogenesis of these headaches. The principal aim of this study was to investigate if the phosphodiesterase inhibitor Ibudilast (Ibu) and 1α,25-dihydroxyvitamin D3 (Vit D3) could interfere with NO release from trigeminal SGCs. Since glutamate is released from activated TG neurons, the ability of glutamate to alter NO release from SGCs was also investigated. To study this, we isolated SGCs from the TG of adult male Sprague-Dawley rats, provoked NO release from SGCs with forskolin (FSK; 0.1, 1, 10 μM), and examined the effect of graded concentrations of Ibu (1, 10, 100 μM), Vit D3 (5, 50, 500 nM), and glutamate (10, 100, 1000 μM). Our results indicate that both Ibu and Vit D3 are capable of attenuating the FSK-mediated increased NO release from SGCs after 48 hours of incubation. Lower glutamate concentrations (10 and 100 μM) significantly decreased NO release not only under basal conditions after 24 and 48 hours, but also after SGCs were stimulated with FSK for 48 hours. In conclusion, NO release from SGCs harvested from the TG can be attenuated by glial modulators and glutamate. As NO is thought to increase TG neuron excitability, the findings suggest that targeting SGCs may provide a novel therapeutic approach for management of craniofacial pain conditions such as migraine in the future.

The aim of the present study was to evaluate the transfection potential of chitosan-coated, green-fluorescent magnetic nanoparticles (MNPs) (chi-MNPs) after encapsulation inside polyethylglycol (PEG)ylated liposomes that produced lipid-encapsulated chitosan-coated MNPs (lip-MNPs), and also to evaluate how these particles would distribute in vivo after systemic injection. The transfection potential of both chi-MNPs and lip-MNPs was evaluated in vitro in rat brain endothelial 4 (RBE4) cells with and without applying a magnetic field. Subsequently, the MNPs were evaluated in vivo in young rats. The in vitro investigations revealed that the application of a magnetic field resulted in an increased cellular uptake of the particles. The lip-MNPs were able to transfect the RBE4 cells with an incidence of approximately 20% of a commercial transfection agent. The in vivo distribution studies revealed that lip-MNPs had superior pharmacokinetic properties due to evasion of the RES, including hepatic Kuppfer cells and macrophages in the spleen. In conclusion, we were able to design a novel lipid-encapsulated MNP with the ability to carry genetic material, with favorable pharmacokinetic properties, and under the influence of a magnetic field with the capability to mediate transfection in vitro.

A patient with chronic lymphocytic leukemia (CLL) treated with chlorambucil and prednisone developed chronic myelocytic leukemia (CML) five years later. An association between the two chronic leukemias has only rarely been reported. In the majority of cases the CLL preceded CML after which the malignancies coexisted morphologically in bone marrow and peripheral blood. In this case we report a suppression of CLL related symptoms and blood findings after the emergence of CML. However, immunophenotypic studies demonstrated a minor remaining population of CLL cells in the peripheral blood.

Antibodies to whole pigeon serum (PS) and pigeon dropping extract (PDE) were investigated in pigeon breeders and controls by an enzyme-linked immunosorbent assay (ELISA). The optimal antigen concentration was in the range of 3-30 microgram protein/ml for both PS and PDE. PDE antibody titres greater than or equal to 10240 were found in three (75%) of four patients with pigeon breeders' disease (PBD) and in 19 (13.6%) of 140 other pigeon breeders (P = 0.011). PS antibody titres greater than or equal to 10240 occurred in all four (100%) PBD patients and in only seven (5.0%) of 140 other breeders (P = 0.0002). In 85 blood donors antibodies in low titres against PS and PDE occurred in 4.7% and 7.1%, respectively. By immunodiffusion three or more precipitin lines were found more often in PBD patients than in other breeders (P = 0.0006), and the highest ELISA antibody titres occurred in patients with precipitating antibodies. No correlation between P blood group phenotypes or anti-P1 antibodies and respiratory symptoms or antibodies to pigeon antigens could be demonstrated.