Risk of Thyroid Cancer in People With Type 1 Diabetes by Autoimmune Thyroid Diseases and Tumor Histology.

Context: Thyroid cancer is the most common endocrine cancer, but little is known about it in type 1 diabetes (T1D) and its potential association with autoimmune diseases. Objective: This study aims to assess the risk of thyroid cancer in adults with long-term T1D compared to individuals without diabetes and the proposed association of thyroid autoimmune diseases with thyroid cancer. Methods: The study included 4758 individuals with T1D participating in the Finnish Diabetic Nephropathy Study and 12 710 controls. Thyroid cancers were obtained from the Finnish Care Registers for Health Care. Results: 27 (0.57%) individuals with T1D had thyroid cancer compared to 27 (0.21%) in the controls (standardized incidence ratio 2.43; 95% confidence interval 1.59-3.56). The absolute increase in incidence was modest, with a 0.36%-unit rise. This translates to 17 additional cases among 4710 individuals with T1D. Cancer type was papillary in 81.5% of individuals with T1D and 88.9% of the controls; the rest were follicular. In T1D the distribution of hypothyreosis was similar between those with (n = 5, 18.5%) and without (18.1%) cancer, but hyperthyreosis was diagnosed more often with thyroid cancer (n = 3, 11.1%) than without (2.3%, P = .003). None of the thyroid cancers were invasive or had metastatic characteristics. Conclusion: Although there is an excess risk of thyroid cancer, it is only marginally increased (0.36%-unit) in individuals with T1D compared to control individuals and was not associated with increased morbidity or mortality. An overdiagnosis effect due to regular health care contacts is the most likely explanation for the higher risk.

Stroke incidence increases with diabetic retinopathy severity and macular edema in type 1 diabetes.

BACKGROUND: As the retina is suggested to mirror the brain, we hypothesized that diabetic retinopathy and macular edema are indicative of stroke risk in type 1 diabetes and sought to assess this association in individuals with type 1 diabetes. METHODS: We included 1,268 adult FinnDiane Study participants with type 1 diabetes (age 38.7 ± 11.8 years, 51.7% men vs. 48.3% women, and 31.5% had diabetic kidney disease), data on baseline diabetic retinopathy severity, and first stroke during our observational follow-up. Retinopathy was graded by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and macular edema as clinically significant (CSME) or not. Strokes identified from registries were confirmed from medical files. Adjusted hazard ratios (HR) for stroke by retinopathy severity and CSME were calculated by Cox models adjusted for clinical confounders, including diabetic kidney disease. RESULTS: During median 18.0 (14.1-19.3) follow-up years, 130 strokes (96 ischemic, 34 hemorrhagic) occurred. With no-very mild (ETDRS 10-20) retinopathy as reference, the adjusted HR for stroke was 1.79 (95%CI 1.02-3.15) in non-proliferative (ETDRS 35-53), and 1.69 (1.02-2.82) in proliferative (ETDRS 61-85) retinopathy. Corresponding adjusted HR for ischemic stroke was 1.68 (0.91-3.10) in non-proliferative and 1.35 (0.77-2.36) in proliferative retinopathy. The adjusted HR for hemorrhagic stroke was 2.84 (0.66-12.28) in non-proliferative and 4.31 (1.16-16.10) in proliferative retinopathy. CSME did not increase HR for any stroke type after adjustment for clinical confounders (data not shown). CONCLUSIONS: Stroke incidence increases with the severity of diabetic retinopathy independently of comorbid conditions, including diabetic kidney disease.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Incidence and risk factors for cancer in people with type 1 diabetes, stratified by stages of diabetic kidney disease: a nationwide Finnish cohort study.

Background: Individuals with type 1 diabetes (T1D) have been reported to have increased overall risk of cancer. In addition, individuals with a kidney transplant/transplantation (KT) have markedly increased cancer risk due to chronic use of immunosuppressive agents. However, it has not been elucidated whether the observed excess cancer risk is related to KT or whether diabetic kidney disease (DKD) per se is a risk factor for cancer in individuals with T1D. Methods: The study included 5035 individuals from the Finnish Diabetic Nephropathy Study (FinnDiane) and 14,061 control individuals without diabetes. We assessed the standardized incidence ratios (SIRs) for cancers in individuals with T1D compared to controls according to DKD status. Cox regression analyses were used to identify potential risk factors for cancer in individuals with type 1 diabetes. Findings: The SIR for overall cancer for all participants was 1.14 (1.05-1.24), for participants without KT 0.92 (0.83-1.01) and for participants with KT 4.78 (4.02-5.64). Participants without KT had in fact a reduced risk of prostate cancer with a SIR of 0.54 (0.37-0.76), cancer of urinary organs 0.41 (0.21-0.73) and respiratory and intrathoracic organs, 0.62 (0.38-0.97). Participants with KT had on the contrary an increased risk of non-melanoma skin cancer, SIR 14.50 (10.99-18.86), cancer in the lymphoid and hematopoietic tissue 5.38 (2.99-8.96), mouth or pharynx 5.13 (2.08-10.66), melanoma 5.12 [2.38-9.72]) and respiratory and intrathoracic organs 2.77 (1.21-5.49). The risk of thyroid cancer was increased both in participants without KT, SIR 2.14 (1.39-3.16) and with KT 5.30 (1.68-12.78). Interpretation: The excess overall cancer risk in individuals with type 1 diabetes is only seen in KT recipients and in thyroid cancer. The individuals without KT seem to have a decreased risk of some forms of cancer. Funding: Folkhälsan Research Foundation, Academy of Finland [316664], Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation [NNF OC0013659], Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation, and Helsinki University Hospital Research Funds [TYH2018207 and TYH 2020305].

Clustering of risk behaviours and associations between risk behaviours and cardio-metabolic risk factors in adult individuals with type 1 diabetes.

AIMS: To assess clustering of risk behaviours and their health determinants. METHODS: Cross-sectional health behaviour and health data were collected from individuals with type 1 diabetes, in the FinnDiane Study. Clustering of risk behaviours was assessed and associations between behaviours and health variables were investigated. RESULTS: Data were available from 956 participants (40 % men, mean age 46 years). Altogether, 4.3 % individuals reported no risk behaviours, while 25.7 %, 37.4 %, 24.7 %, 6.8 %, and 1.0 % reported 1, 2, 3, 4, and 5 risk behaviours, respectively. Reporting ≥4 risk behaviours occurred more frequently than expected by chance. Dietary non-adherence was most frequently reported (84.4 %), followed by low LTPA (54.4 %), poor sleep (41.9 %), high alcohol consumption (15.2 %), and smoking (11.2 %). Adjusted for confounders, relative to ≤1 risk behaviour, reporting ≥2 risk behaviours was associated with higher BMI, waist circumference, and diastolic blood pressure. Having ≥3 risk behaviours was associated with larger waist-hip ratio, and higher HbA1c and triglyceride concentration; ≥4 risk behaviours was associated with higher cholesterol concentration. Of the health behaviours, low LTPA had the highest number of deleterious health associations. CONCLUSIONS: Accumulation of risk behaviors increases negative health outcomes. Exhibiting ≥2 risk behaviours or low LTPA was associated with multiple adverse outcomes.

Impact of RYGB surgery on plasma immunoglobulins: association between blood pressure and glucose levels six months after surgery.

We aimed to study levels of natural antibodies in plasma, and their associations to clinical and fecal biomarkers, before and 6 months after Roux-en-Y gastric bypass (RYGB) surgery. Thirty individuals with obesity [16 type 2 diabetic, 14 non-diabetic (ND)] had RYGB surgery. Total plasma IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts, Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44), and phosphocholine were measured using chemiluminescence immunoassay. Associations between plasma and fecal antibodies as well as clinical markers were analyzed. RYGB surgery reduced blood pressure, and the glycemic state was improved. A higher level of diastolic blood pressure was associated with lower plasma antibodies to oxLDL after surgery. Also, lower level of glucose markers associated with lower level of plasma antibodies to bacterial virulence factors. Antibodies to oxLDL decreased after surgery, and positive association between active serum lipopolysaccharide and specific oxLDL antibodies was detected. Total IgG levels decreased after surgery, but only in ND individuals. Reduced level of total plasma IgG, improved state of hypertension and hyperglycemia and their associations with decreased levels of specific antibodies in plasma, suggest an improved state of systemic inflammation after RYGB surgery.

Medication profiling in women with type 1 diabetes highlights the importance of adequate, guideline-based treatment in low-risk groups.

Effective treatment may prevent kidney complications, but women might be underprescribed. Novel, data-driven insights into prescriptions and their relationship with kidney health in women with type 1 diabetes may help to optimize treatment. We identified six medication profiles in 1164 women from the FinnDiane Study with normal albumin excretion rate based on clusters of their baseline prescription data using a self-organizing map. Future rapid kidney function decline was defined as an annual estimated glomerular filtration rate (eGFR) loss > 3 ml/min/1.73 m2 after baseline. Two profiles were associated with future decline: Profile ARB with the highest proportion of angiotensin receptor blockers (odds ratio [OR] 2.75, P = 0.02) and highly medicated women in profile HighMed (OR 2.55, P = 0.03). Compared with profile LowMed (low purchases of all), profile HighMed had worse clinical characteristics, whereas in profile ARB only systolic blood pressure was elevated. Importantly, the younger women in profile ARB with fewer kidney protective treatments developed a rapid decline despite otherwise similar baseline characteristics to profile ACE & Lipids (the highest proportions of ACE inhibitors and lipid-modifying agents) without a future rapid decline. In conclusion, medication profiles identified different future eGFR trajectories in women with type 1 diabetes revealing potential treatment gaps for younger women.

Rationale and design of a randomised phase III registration trial investigating finerenone in participants with type 1 diabetes and chronic kidney disease: The FINE-ONE trial.

AIMS: Despite guideline-recommended treatments, including renin angiotensin system inhibition, up to 40 % of individuals with type 1 diabetes develop chronic kidney disease (CKD) putting them at risk of kidney failure. Finerenone is approved to reduce the risk of kidney failure in individuals with type 2 diabetes. We postulate that finerenone will demonstrate benefits on kidney outcomes in people with type 1 diabetes. METHODS: FINE-ONE (NCT05901831) is a randomised, placebo-controlled, double-blind phase III trial of 7.5 months' duration in ∼220 adults with type 1 diabetes, urine albumin/creatinine ratio (UACR) of ≥ 200-< 5000 mg/g (≥ 22.6-< 565 mg/mmol) and eGFR of ≥ 25-< 90 ml/min/1.73 m2. RESULTS: The primary endpoint is relative change in UACR from baseline over 6 months. UACR is used as a bridging biomarker (BB), since the treatment effect of finerenone on UACR was associated with its efficacy on kidney outcomes in the type 2 diabetes trials. Based on regulatory authority feedback, UACR can be used as a BB for kidney outcomes to support registration of finerenone in type 1 diabetes, provided necessary criteria are met. Secondary outcomes include incidences of treatment-emergent adverse events, treatment-emergent serious adverse events and hyperkalaemia. CONCLUSIONS: FINE-ONE will evaluate the efficacy and safety of finerenone in type 1 diabetes and CKD. Finerenone could become the first registered treatment for CKD associated with type 1 diabetes in almost 30 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT05901831.

Capturing the Kidney Transcriptome by Urinary Extracellular Vesicles-From Pre-Analytical Obstacles to Biomarker Research.

Urinary extracellular vesicles (uEV) hold non-invasive RNA biomarkers for genitourinary tract diseases. However, missing knowledge about reference genes and effects of preanalytical choices hinder biomarker studies. We aimed to assess how preanalytical variables (urine storage temperature, isolation workflow) affect diabetic kidney disease (DKD)-linked miRNAs or kidney-linked miRNAs and mRNAs (kidney-RNAs) in uEV isolates and to discover stable reference mRNAs across diverse uEV datasets. We studied nine raw and normalized sequencing datasets including healthy controls and individuals with prostate cancer or type 1 diabetes with or without albuminuria. We focused on kidney-RNAs reviewing literature for DKD-linked miRNAs from kidney tissue, cell culture and uEV/urine experiments. RNAs were analyzed by expression heatmaps, hierarchical clustering and selecting stable mRNAs with normalized counts (>200) and minimal coefficient of variation. Kidney-RNAs were decreased after urine storage at -20 °C vs. -80 °C. Isolation workflows captured kidney-RNAs with different efficiencies. Ultracentrifugation captured DKD -linked miRNAs that separated healthy and diabetic macroalbuminuria groups. Eleven mRNAs were stably expressed across the datasets. Hence, pre-analytical choices had variable effects on kidney-RNAs-analyzing kidney-RNAs complemented global correlation, which could fade differences in some relevant RNAs. Replicating prior DKD-marker results and discovery of candidate reference mRNAs encourages further uEV biomarker studies.

Cardiometabolic risk management: insights from a European Society of Cardiology Cardiovascular Round Table.

Metabolic comorbidities are common in patients with cardiorenal disease; they can cause atherosclerotic cardiovascular disease (ASCVD), speed progression, and adversely affect prognosis. Common comorbidities are Type 2 diabetes mellitus (T2DM), obesity/overweight, chronic kidney disease (CKD), and chronic liver disease. The cardiovascular system, kidneys, and liver are linked to many of the same risk factors (e.g. dyslipidaemia, hypertension, tobacco use, diabetes, and central/truncal obesity), and shared metabolic and functional abnormalities lead to damage throughout these organs via overlapping pathophysiological pathways. The COVID-19 pandemic has further complicated the management of cardiometabolic diseases. Obesity, T2DM, CKD, and liver disease are associated with increased risk of poor outcomes of COVID-19 infection, and conversely, COVID-19 can lead to worsening of pre-existing ASCVD. The high rates of these comorbidities highlight the need to improve recognition and treatment of ASCVD in patients with obesity, insulin resistance or T2DM, chronic liver diseases, and CKD and equally, to improve recognition and treatment of these diseases in patients with ASCVD. Strategies to prevent and manage cardiometabolic diseases include lifestyle modification, pharmacotherapy, and surgery. There is a need for more programmes at the societal level to encourage a healthy diet and physical activity. Many pharmacotherapies offer mechanism-based approaches that can target multiple pathophysiological pathways across diseases. These include sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, selective mineralocorticoid receptor antagonists, and combined glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist. Non-surgical and surgical weight loss strategies can improve cardiometabolic disorders in individuals living with obesity. New biomarkers under investigation may help in the early identification of individuals at risk and reveal new treatment targets.

Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease.

Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney-derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed ∼200 uEV mRNA samples from clinical studies by genome-wide sequencing to discover mechanisms and candidate biomarkers of diabetic kidney disease (DKD) in Type 1 diabetes (T1D) with replication in Type 1 and 2 diabetes. Sequencing reproducibly showed >10,000 mRNAs with similarity to kidney transcriptome. T1D DKD groups showed 13 upregulated genes prevalently expressed in proximal tubules, correlated with hyperglycemia and involved in cellular/oxidative stress homeostasis. We used six of them (GPX3, NOX4, MSRB, MSRA, HRSP12, and CRYAB) to construct a transcriptional "stress score" that reflected long-term decline of kidney function and could even identify normoalbuminuric individuals showing early decline. We thus provide workflow and web resource for studying uEV transcriptomes in clinical urine samples and stress-linked DKD markers as potential early non-invasive biomarkers or drug targets.

Long-chain polyphosphates inhibit type I interferon signaling and augment LPS-induced cytokine secretion in human leukocytes.

Inorganic polyphosphates are evolutionarily conserved bioactive phosphate polymers found as various chain lengths in all living organisms. In mammals, polyphosphates play a vital role in the regulation of cellular metabolism, coagulation, and inflammation. Long-chain polyphosphates are found along with endotoxins in pathogenic gram-negative bacteria and can participate in bacterial virulence. We aimed to investigate whether exogenously administered polyphosphates modulate human leukocyte function in vitro by treating the cells with 3 different chain lengths of polyphosphates (P14, P100, and P700). The long-chain polyphosphates, P700, had a remarkable capacity to downregulate type I interferon signaling dose dependently in THP1-Dual cells while only a slight elevation could be observed in the NF-κB pathway with the highest dose of P700. P700 treatment decreased lipopolysaccharide-induced IFNß transcription and secretion, reduced STAT1 phosphorylation, and downregulated subsequent interferon-stimulated gene expression in primary human peripheral blood mononuclear cells. P700 also augmented lipopolysaccharide-induced secretion of IL-1α, IL-1ß, IL-4, IL-5, IL-10, and IFNγ. Furthermore, P700 has previously been reported to increase the phosphorylation of several intracellular signaling mediators, such as AKT, mTOR, ERK, p38, GSK3α/ß, HSP27, and JNK pathway components, which was supported by our findings. Taken together, these observations demonstrate the extensive modulatory effects P700 has on cytokine signaling and the inhibitory effects specifically targeted to type I interferon signaling in human leukocytes.

The impact of diabetic nephropathy and severe diabetic retinopathy on chronic limb threatening ischemia risk in individuals with type 1 diabetes: a nationwide, population study.

Background: The prevalence, incidence and risk factors and especially the effect of diabetic nephropathy (DN) and diabetic retinopathy on the risk of chronic limb threatening ischemia (CLTI) have been sparsely studied in individuals with type 1 diabetes (T1D). Methods: The prospective cohort study consisted of 4697 individuals with T1D from the nationwide Finnish Diabetic Nephropathy (FinnDiane) Study. Medical records were thoroughly reviewed in order to ascertain all CLTI events. The key risk factors were DN and severe diabetic retinopathy (SDR). Findings: There were 319 events of confirmed CLTI, 102 prevalent events at baseline and 217 incident events during the follow-up of 11.9 (IQR 9.3-13.8) years. The 12-year cumulative incidence of CLTI was 4.6% (95% CI 4.0-5.3). Risk factors included presence of DN, SDR, age, duration of diabetes, HbA1c, systolic blood pressure, triglycerides and current smoking. Sub-hazard ratios (SHRs) according to combinations of DN status and presence (+) or absence (-) of SDR were 4.8 (2.0-11.7) for normoalbuminuria/SDR+, 3.2 (1.1-9.4) for microalbuminuria/SDR-, 11.9 (5.4-26.5) for microalbuminuria/SDR+, 8.7 (3.2-23.2) for macroalbuminuria/SDR-, 15.6 (7.4-33.0) for macroalbuminuria/SDR+ and 37.9 (17.2-78.9) for kidney failure compared with individuals with normal albumin excretion rate and without SDR. Interpretation: Diabetic nephropathy, especially kidney failure, is associated with high risk of limb threatening ischemia in individuals with T1D. The risk of CLTI increases gradually according to the severity of diabetic nephropathy. Also, diabetic retinopathy is independently and additively associated with high risk of CLTI. Funding: This research was funded by grants from Folkhälsan Research Foundation, Academy of Finland (316664), Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation (NNF OC0013659), Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation and Helsinki University Hospital Research Funds.

L-type calcium channel blocker increases VEGF concentrations in retinal cells and human serum.

OBJECTIVE: Vascular endothelial growth factor (VEGF) plays a key role in diabetic retinopathy (DR). Previously, we have reported an association between mutations in a gene coding for the L-type calcium channel subunit, VEGF and DR. L-type calcium channel blockers (LTCCBs) have been widely used as antihypertensive medication (AHM), but their association with VEGF and DR is still unclear. Therefore, we explored the effect of LTCCBs compared to other AHMs on VEGF concentrations in retinal cells and human serum. Furthermore, we evaluated the association between the use of LTCCBs and the risk of severe diabetic eye disease (SDED). RESEARCH DESIGN AND METHODS: Müller cells (MIO-M1) were cultured as per recommended protocol and treated with LTCCBs and other AHMs. VEGF secreted from cells were collected at 24 hours intervals. In an interventional study, 39 individuals received LTCCBs or other AHM for four weeks with a four-week wash-out placebo period between treatments. VEGF was measured during the medication and placebo periods. Finally, we evaluated the risk of SDED associated with LTCCB usage in 192 individuals from the FinnDiane Study in an observational setting. RESULTS: In the cell cultures, the medium VEGF concentration increased time-dependently after amlodipine (P<0.01) treatment, but not after losartan (P>0.01), or lisinopril (P>0.01). Amlodipine, but no other AHM, increased the serum VEGF concentration (P<0.05) during the interventional clinical study. The usage of LTCCB was not associated with the risk of SDED in the observational study. CONCLUSIONS: LTCCB increases VEGF concentrations in retinal cells and human serum. However, the usage of LTCCBs does not appear to be associated with SDED in adults with type 1 diabetes.

The association between blood oxygen saturation and baroreflex sensitivity in adults with type 1 diabetes with and without albuminuria.

BACKGROUND: Low baroreflex sensitivity is an indicator of early cardiovascular autonomic neuropathy. We explored the association between baroreflex sensivity and blood oxygen saturation (SpO2) in type 1 diabetes and various degrees of microvascular disease. METHODS: In this Danish-Finnish cross-sectional multicentre study, baroreflex sensivity and SpO2 (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, HbA1c, 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 SpO2 before adjustment (% increase per one % increase in SpO2 = 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). SpO2 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, SpO2 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 SpO2 in type 1 diabetes. The present study support the hypothesis that hypoxia could be a therapeutic target in persons with type 1 diabetes.

CVOT Summit 2022 Report: new cardiovascular, kidney, and glycemic outcomes.

The 8th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Kidney, and Glycemic Outcomes was held virtually on November 10-12, 2022. Following the tradition of previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed outcomes trials as well as key trials important to the cardiovascular (CV) field. This year's focus was on the results of the DELIVER, EMPA-KIDNEY and SURMOUNT-1 trials and their implications for the treatment of heart failure (HF) and chronic kidney disease (CKD) with sodium-glucose cotransporter-2 (SGLT2) inhibitors and obesity with glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. A broad audience of primary care physicians, diabetologists, endocrinologists, cardiologists, and nephrologists participated online in discussions on new consensus recommendations and guideline updates on type 2 diabetes (T2D) and CKD management, overcoming clinical inertia, glycemic markers, continuous glucose monitoring (CGM), novel insulin preparations, combination therapy, and reclassification of T2D. The impact of cardiovascular outcomes on the design of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) trials, as well as the impact of real-world evidence (RWE) studies on the confirmation of CVOT outcomes and clinical trial design, were also intensively discussed. The 9th Cardiovascular Outcome Trial Summit will be held virtually on November 23-24, 2023 ( http://www.cvot.org ).

Total fecal IgA levels increase and natural IgM antibodies decrease after gastric bypass surgery.

Obesity is associated with low-grade inflammation and increased systemic oxidative stress. Roux-en-Y gastric bypass (RYGB) surgery is known to ameliorate the obesity-induced metabolic dysfunctions. We aimed to study the levels of natural antibodies in feces, before and 6 months after RYGB surgery in obese individuals with and without type 2 diabetes (T2D). Sixteen individuals with T2D and 14 non-diabetic (ND) individuals were operated. Total IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts (MAA adducts), Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44) and phosphocholine (PCho) were measured using chemiluminescence immunoassay. Total fecal IgA was elevated, while total IgM and IgG were not affected by the surgery. Fecal natural IgM specific to oxLDL decreased significantly in both T2D and ND individuals, while fecal IgM to Rgp44 and PCho decreased significantly in T2D individuals. A decrease in IgG to MAA-LDL, Rgp44 and PCho was detected. RYGB surgery increases the levels of total fecal IgA and decreases fecal natural IgG and IgM antibodies specific to oxLDL. Natural antibodies and IgA are important in maintaining the normal gut homeostasis and first-line defense against microbes, and their production is markedly altered with RYGB surgery.

Markers of early vascular aging are not associated with cryptogenic ischemic stroke in the young: A case-control study.

BACKGROUND AND PURPOSE: We aimed to assess the association between covert atherosclerosis, arterial stiffness, and early-onset cryptogenic ischemic stroke (CIS) in a prospective case-control study. METHODS: We enrolled 123 young CIS patients (median age 41 years; 42% women) and 123 age- and sex-matched controls. Carotid intima-media thickness (CIMT), Augmentation Index (AIx), central pulse wave velocity (PWV), and subendocardial viability ratio (SEVR) were compared between patients and controls. Conditional logistic regression was used adjusting for age, systolic blood pressure, diastolic blood pressure, current smoking, total cholesterol/high-density lipoprotein cholesterol (Total-C/HDL-C) ratio, and glycated albumin to assess the independent association between CIMT, arterial stiffness and CIS. RESULTS: Patients with higher CIMT and PWV were older, more often men and they had more frequently well-documented risk factors, lower HDL and higher Total-C/HDL-C ratio compared to other tertiles. In univariate comparisons, we found no differences between patients and controls regarding CIMT, AIx, or PWV. In the entire cohort, patients had a significantly lower SEVR compared to controls (146.3%, interquartile range [IQR] 125.7-170.3 vs. 158.0%, IQR 141.3-181.0, P=0.010). SEVR was lower also in women compared to their controls (132.0%, IQR 119.4-156.1 vs. 158.7%, IQR 142.0-182.8, P=0.001) but no significant difference appeared between male patients and male controls. However, after adjusting for comorbidities and laboratory values these significant differences were lost (odds ratio [OR] 1.52, 95% confidence interval [CI] 0.47-4.91) in the entire cohort and OR 3.89, 95% CI 0.30-50.80 in women). CONCLUSIONS: Higher CIMT and PWV were associated to higher age, male sex, and several well-documented cardiovascular risk factors. However, in this study we could not prove that either covert atherosclerosis or arterial stiffness contribute to pathogenesis of early-onset CIS.

Apolipoprotein C-III predicts cardiovascular events and mortality in individuals with type 1 diabetes and albuminuria.

OBJECTIVES: We studied apolipoprotein C-III (apoC-III) in relation to diabetic kidney disease (DKD), cardiovascular outcomes, and mortality in type 1 diabetes. METHODS: The cohort comprised 3966 participants from the prospective observational Finnish Diabetic Nephropathy Study. Progression of DKD was determined from medical records. A major adverse cardiac event (MACE) was defined as acute myocardial infarction, coronary revascularization, stroke, or cardiovascular mortality through 2017. Cardiovascular and mortality data were retrieved from national registries. RESULTS: ApoC-III predicted DKD progression independent of sex, diabetes duration, blood pressure, HbA1c , smoking, LDL-cholesterol, lipid-lowering medication, DKD category, and remnant cholesterol (hazard ratio [HR] 1.43 [95% confidence interval 1.05-1.94], p = 0.02). ApoC-III also predicted the MACE in a multivariable regression analysis; however, it was not independent of remnant cholesterol (HR 1.05 [0.81-1.36, p = 0.71] with remnant cholesterol; 1.30 [1.03-1.64, p = 0.03] without). DKD-specific analyses revealed that the association was driven by individuals with albuminuria, as no link between apoC-III and the outcome was observed in the normal albumin excretion or kidney failure categories. The same was observed for mortality: Individuals with albuminuria had an adjusted HR of 1.49 (1.03-2.16, p = 0.03) for premature death, while no association was found in the other groups. The highest apoC-III quartile displayed a markedly higher risk of MACE and death than the lower quartiles; however, this nonlinear relationship flattened after adjustment. CONCLUSIONS: The impact of apoC-III on MACE risk and mortality is restricted to those with albuminuria among individuals with type 1 diabetes. This study also revealed that apoC-III predicts DKD progression, independent of the initial DKD category.

Kidney oxygenation, perfusion and blood flow in people with and without type 1 diabetes.

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 (R2*, 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 m2 versus 88 ± 15 mL/min/1.73 m2;  P = .12), although not significantly. Mean medullary R2* was lower in T1D (34 ± 6/s versus 38 ± 5/s; P < .01) corresponding to a higher oxygenation. R2* 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.