Circadian desynchrony and glucose metabolism.

The circadian timing system controls glucose metabolism in a time-of-day dependent manner. In mammals, the circadian timing system consists of the main central clock in the bilateral suprachiasmatic nucleus (SCN) of the anterior hypothalamus and subordinate clocks in peripheral tissues. The oscillations produced by these different clocks with a period of approximately 24-h are generated by the transcriptional-translational feedback loops of a set of core clock genes. Glucose homeostasis is one of the daily rhythms controlled by this circadian timing system. The central pacemaker in the SCN controls glucose homeostasis through its neural projections to hypothalamic hubs that are in control of feeding behavior and energy metabolism. Using hormones such as adrenal glucocorticoids and melatonin and the autonomic nervous system, the SCN modulates critical processes such as glucose production and insulin sensitivity. Peripheral clocks in tissues, such as the liver, muscle, and adipose tissue serve to enhance and sustain these SCN signals. In the optimal situation all these clocks are synchronized and aligned with behavior and the environmental light/dark cycle. A negative impact on glucose metabolism becomes apparent when the internal timing system becomes disturbed, also known as circadian desynchrony or circadian misalignment. Circadian desynchrony may occur at several levels, as the mistiming of light exposure or sleep will especially affect the central clock, whereas mistiming of food intake or physical activity will especially involve the peripheral clocks. In this review, we will summarize the literature investigating the impact of circadian desynchrony on glucose metabolism and how it may result in the development of insulin resistance. In addition, we will discuss potential strategies aimed at reinstating circadian synchrony to improve insulin sensitivity and contribute to the prevention of type 2 diabetes.

Comparing advanced hybrid closed loop therapy and standard insulin therapy in pregnant women with type 1 diabetes (CRISTAL): a parallel-group, open-label, randomised controlled trial.

BACKGROUND: Advanced hybrid closed loop (AHCL) therapy can improve glycaemic control in pregnant women with type 1 diabetes. However, data are needed on the efficacy and safety of AHCL systems as these systems, such as the MiniMed 780G, are not currently approved for use in pregnant women. We aimed to investigate whether the MiniMed 780G can improve glycaemic control with less hypoglycaemia in pregnant women with type 1 diabetes. METHODS: CRISTAL was a double-arm, parallel-group, open-label, randomised controlled trial conducted in secondary and tertiary care specialist endocrinology centres at 12 hospitals (11 in Belgium and one in the Netherlands). Pregnant women aged 18-45 years with type 1 diabetes were randomly assigned (1:1) to AHCL therapy (MiniMed 780G) or standard insulin therapy (standard of care) at a median of 10·1 (IQR 8·6-11·6) weeks of gestation. Randomisation was done centrally with minimisation dependent on baseline HbA1c, insulin administration method, and centre. Participants and study teams were not masked to group allocation. The primary outcome was proportion of time spent in the pregnancy-specific target glucose range (3·5-7·8 mmol/L), measured by continuous glucose monitoring (CGM) at 14-17 weeks, 20-23 weeks, 26-29 weeks, and 33-36 weeks. Key secondary outcomes were overnight time in target range, and time below glucose range (<3·5 mmol/L) overall and overnight. Analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT04520971). FINDINGS: Between Jan 15, 2021 and Sept 30, 2022, 101 participants were screened, and 95 were randomly assigned to AHCL therapy (n=46) or standard insulin therapy (n=49). 43 patients assigned to AHCL therapy and 46 assigned to standard insulin therapy completed the study. At baseline, 91 (95·8%) participants used insulin pumps, and the mean HbA1c was 6·5% (SD 0·6). The mean proportion of time spent in the target range (averaged over four time periods) was 66·5% (SD 10·0) in the AHCL therapy group compared with 63·2% (12·4) in the standard insulin therapy group (adjusted mean difference 1·88 percentage points [95% CI -0·82 to 4·58], p=0·17). Overnight time in the target range was higher (adjusted mean difference 6·58 percentage points [95% CI 2·31 to 10·85], p=0·0026), and time below range overall (adjusted mean difference -1·34 percentage points [95% CI, -2·19 to -0·49], p=0·0020) and overnight (adjusted mean difference -1·86 percentage points [95% CI -2·90 to -0·81], p=0·0005) were lower with AHCL therapy than with standard insulin therapy. Participants assigned to AHCL therapy reported higher treatment satisfaction. No unanticipated safety events occurred with AHCL therapy. INTERPRETATION: In pregnant women starting with tighter glycaemic control, AHCL therapy did not improve overall time in target range but improved overnight time in target range, reduced time below range, and improved treatment satisfaction. These data suggest that the MiniMed 780G can be safely used in pregnancy and provides some additional benefits compared with standard insulin therapy; however, it will be important to refine the algorithm to better align with pregnancy requirements. FUNDING: Diabetes Liga Research Fund and Medtronic.

Basal cortisol in relation to metyrapone confirmation in predicting adrenal insufficiency after pituitary surgery.

PURPOSE: Pituitary surgery can lead to post-surgical adrenal insufficiency with the need for glucocorticoid replacement and significant disease related burden. In patients who do not receive hydrocortisone replacement before surgery, at our center, an early morning plasma cortisol concentration using a cut-off value of 450 nmol/L 3 days after surgery (POD3) is used to guide the need for hydrocortisone replacement until dynamic confirmatory testing using metyrapone. The aim of this study was to critically assess the currently used diagnostic and treatment algorithm in patients undergoing pituitary surgery in our pituitary reference center. METHODS: Retrospective analysis of all patients with a POD3 plasma cortisol concentration < 450 nmol/L who received hydrocortisone replacement and a metyrapone test after 3 months. Plasma cortisol concentration was measured using an electrochemiluminescence immunoassay (Roche). All patients who underwent postoperative testing using metyrapone at Amsterdam UMC between January 2018 and February 2022 were included. Patients with Cushing's disease or those with hydrocortisone replacement prior to surgery were excluded. RESULTS: Ninety-five patients were included in the analysis. The postoperative cortisol concentration above which no patient had adrenal insufficiency (i.e. 11-deoxycortisol > 200 nmol/L) was 357 nmol/L (Sensitivity 100%, Specificity 31%, PPV:32%, NPV:100%). This translates into a 28% reduction in the need for hydrocortisone replacement compared with the presently used cortisol cut-off value of 450 nmol/L. CONCLUSION: Early morning plasma cortisol cut-off values lower than 450 nmol/L can safely be used to guide the need for hydrocortisone replacement after pituitary surgery.

Perioperative management of long-acting glucagon-like peptide-1 (GLP-1) receptor agonists: concerns for delayed gastric emptying and pulmonary aspiration.

Prescriptions and use of glucagon-like peptide-1 (GLP-1) receptor agonists are increasing dramatically, as indications are expanding from the treatment of diabetes mellitus to weight loss for people with obesity. As GLP-1 receptor agonists delay gastric emptying, perioperative healthcare practitioners could be concerned about an increased risk for pulmonary aspiration during general anaesthesia. We summarise relevant medical literature and provide evidence-based recommendations for perioperative care for people taking GLP-1 receptor agonists. GLP-1 receptor agonists delay gastric emptying; however, ongoing treatment attenuates this effect. The risk of aspiration during general anaesthesia is unknown. However, we advise caution in patients who recently commenced on GLP-1 receptor agonists. After over 12 weeks of treatment, standard fasting times likely suffice to manage the risk of pulmonary aspiration for most otherwise low-risk patients.

Effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation on offspring outcomes: a systematic review of the evidence.

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation. Methods: We systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17th 2023 and the Teratology Information Service (TIS) of Switzerland on February 6th 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion. Results: We included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available. Conclusion/interpretation: We found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies. Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=219877.

Continuous glucose monitoring metrics and pregnancy outcomes in insulin-treated diabetes: A post-hoc analysis of the GlucoMOMS trial.

AIM: To investigate the association between continuous glucose monitoring (CGM) metrics and perinatal outcomes in insulin-treated diabetes mellitus in pregnancy. MATERIALS AND METHODS: In a post-hoc analysis of the GlucoMOMS randomized controlled trial, we investigated the association between the metrics of an offline, intermittent CGM, glycated haemoglobin (HbA1c) and perinatal outcomes per trimester in different types of diabetes (type 1, 2 or insulin-treated gestational diabetes mellitus [GDM]). Data were analysed using multivariable binary logistic regression. Outcomes of interest were neonatal hypoglycaemia, pre-eclampsia, preterm birth, large for gestational age (LGA) and Neonatal Intensive Care Unit (NICU) admission. The glucose target range was defined as 3.5-7.8 mmol/L (63-140 mg/dL). RESULTS: Of the 147 participants (N = 50 type 1 diabetes, N = 94 type 2 diabetes/insulin-treated GDM) randomized to the CGM group of the GlucoMOMS trial, 115 participants had CGM metrics available and were included in the current study. We found that, in pregnancies with type 1 diabetes, a higher second trimester mean glucose was associated with LGA (odds ratio 2.6 [95% confidence interval 1.1-6.2]). In type 2 and insulin-treated gestational diabetes, an increased area under the curve above limit was associated with LGA (odds ratio 10.0 [95% confidence interval 1.4-72.8]). None of the CGM metrics were associated with neonatal hypoglycaemia, pre-eclampsia, shoulder dystocia, preterm birth and NICU admission rates for pregnancies complicated by any type of diabetes. CONCLUSION: In this study, in type 2 diabetes or insulin-treated GDM, the glucose increased area under the curve above limit was associated with increased LGA. In type 1 diabetes, the mean glucose was the major determinant of LGA. Our study found no evidence that other CGM metrics determined adverse pregnancy outcomes.

Effect of Postmenopausal Hormone Therapy on Glucose Regulation in Women With Type 1 or Type 2 Diabetes: A Systematic Review and Meta-analysis.

BACKGROUND: Blood glucose regulation in women with diabetes may change during and after menopause, which could be attributed, in part, to decreased estrogen levels. PURPOSE: To determine the effect of postmenopausal hormone therapy (HT) on HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering drugs in women with type 1 and women with type 2 diabetes. DATA SOURCES: We conducted a systematic search of MEDLINE, Embase, Scopus, the Cochrane Library, and the ClinicalTrials.gov registry to identify randomized controlled trials (RCTs). STUDY SELECTION: We selected RCTs on the effect of HT containing estrogen therapy in postmenopausal women (≥12 months since final menstrual period) with type 1 or type 2 diabetes. DATA EXTRACTION: Data were extracted for the following outcomes: HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering medication. DATA SYNTHESIS: Nineteen RCTs were included (12 parallel-group trials and 7 crossover trials), with a total of 1,412 participants, of whom 4.0% had type 1 diabetes. HT reduced HbA1c (mean difference -0.56% [95% CI -0.80, -0.31], -6.08 mmol/mol [95% CI -8.80, -3.36]) and fasting glucose (mean difference -1.15 mmol/L [95% CI -1.78, -0.51]). LIMITATIONS: Of included studies, 50% were at high risk of bias. CONCLUSIONS: When postmenopausal HT is considered for menopausal symptoms in women with type 2 diabetes, HT is expected to have a neutral-to-beneficial impact on glucose regulation. Evidence for the effect of postmenopausal HT in women with type 1 diabetes was limited.

Glucose variability and mood in people with type 1 diabetes using ecological momentary assessment.

OBJECTIVE: Mood fluctuations related to blood glucose excursions are a commonly reported source of diabetes-distress, but research is scarce. We aimed to assess the relationship between real-time glucose variability and mood in adults with type 1 diabetes (T1D) using ecological momentary assessments. METHODS: In this prospective observational study, participants wore a masked continuous glucose monitor and received prompts on their smartphone 6 times a day to answer questions about their current mood (Profile Of Mood States (POMS)-SF (dimensions: Anxiety, Depressive symptoms, Anger, Fatigue, Vigor)) for 14 days. Mixed model analyses examined associations over time between daily Coefficient of Variation (CV) of blood glucose and mean and variability (CV) of POMS scores. Further, within-person differences in sleep and nocturnal hypoglycemia were explored. RESULTS: 18 people with T1D (10 female, mean age 44.3 years) participated. A total of 264 out of 367 days (70.2%) could be included in the analyses. No overall significant associations were found between CV of blood glucose and mean and CV of POMS scores, however, nocturnal hypoglycemia moderated the associations between CV of blood glucose and POMS scales (mean Fatigue Estimate 1.998, p < .006, mean Vigor Estimate -3.308, p < .001; CV Anger Estimate 0.731p = 0.02, CV Vigor Estimate -0.525, p = .006). CONCLUSION: We found no overall relationship between real-time glycemic variability and mood per day. Further research into within-person differences such as sleep and nocturnal hypoglycemia is warranted.

Management of type 1 diabetes in pregnancy: update on lifestyle, pharmacological treatment, and novel technologies for achieving glycaemic targets.

Glucose concentrations within target, appropriate gestational weight gain, adequate lifestyle, and, if necessary, antihypertensive treatment and low-dose aspirin reduces the risk of pre-eclampsia, preterm delivery, and other adverse pregnancy and neonatal outcomes in pregnancies complicated by type 1 diabetes. Despite the increasing use of diabetes technology (ie, continuous glucose monitoring and insulin pumps), the target of more than 70% time in range in pregnancy (TIRp 3·5-7·8 mmol/L) is often reached only in the final weeks of pregnancy, which is too late for beneficial effects on pregnancy outcomes. Hybrid closed-loop (HCL) insulin delivery systems are emerging as promising treatment options in pregnancy. In this Review, we discuss the latest evidence on pre-pregnancy care, management of diabetes-related complications, lifestyle recommendations, gestational weight gain, antihypertensive treatment, aspirin prophylaxis, and the use of novel technologies for achieving and maintaining glycaemic targets during pregnancy in women with type 1 diabetes. In addition, the importance of effective clinical and psychosocial support for pregnant women with type 1 diabetes is also highlighted. We also discuss the contemporary studies examining HCL systems in type 1 diabetes during pregnancies.

Closed-loop insulin delivery in pregnant women with type 1 diabetes (CRISTAL): a multicentre randomized controlled trial - study protocol.

BACKGROUND: Despite increasing use of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII, insulin pumps) in type 1 diabetes (T1D) in pregnancy, achieving recommended pregnancy glycaemic targets (3.5-7.8 mmol/L or 63-140 mg/dL) remains challenging. Consequently, the risk of adverse pregnancy outcomes remains high. Outside pregnancy, hybrid closed-loop (HCL) insulin delivery systems have led to a paradigm shift in the management of T1D, with 12% higher time in glucose target range (TIR) compared to conventional CSII. However, most commercially available HCL systems are currently not approved for use in pregnancy. This study aims to evaluate the efficacy, safety and cost-effectiveness of the MiniMed™ 780G HCL system (Medtronic) in T1D in pregnancy. METHODS: In this international, open-label, randomized controlled trial (RCT), we will compare the MiniMed™ 780G HCL system to standard of care (SoC) in T1D in pregnancy. Women aged 18-45 years with T1D diagnosis of at least one year, HbA1c ≤ 86 mmol/mol (≤ 10%), and confirmed singleton pregnancy up to 11 weeks 6 days will be eligible. After providing written informed consent, all participants will wear a similar CGM system (Guardian™ 3 or Guardian™ 4 CGM) during a 10-day run-in phase. After the run-in phase, participants will be randomised 1:1 to 780G HCL (intervention) or SoC [control, continuation of current T1D treatment with multiple daily injections (MDI) or CSII and any type of CGM] stratified according to centre, baseline HbA1c (< 53 vs. ≥ 53 mmol/mol or < 7 vs. ≥ 7%), and method of insulin delivery (MDI or CSII). The primary outcome will be the time spent within the pregnancy glucose target range, as measured by the CGM at four time points in pregnancy: 14-17, 20-23, 26-29, and 33-36 weeks. Prespecified secondary outcomes will be overnight TIR, time below range (TBR: <3.5 mmol/L or < 63 mg/dL), and overnight TBR. Other outcomes will be exploratory. The planned sample size is 92 participants. The study will end after postpartum discharge from hospital. Analyses will be performed according to intention-to-treat as well as per protocol. DISCUSSION: This large RCT will evaluate a widely used commercially available HCL system in T1D in pregnancy. Recruitment began in January 2021 and was completed in October 2022. Study completion is expected in May 2023. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04520971. Registration date: August 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04520971.

Type 1 and other types of diabetes mellitus in the perioperative period. What the anaesthetist should know.

Diabetes mellitus is often treated as a uniform disease in the perioperative period. Type 2 diabetes is most commonly encountered, and only a minority of surgical patients have been diagnosed with another type of diabetes. Patients with a specific type of diabetes can be particularly prone to perioperative glycaemic dysregulation. In addition, certain type-related features and pitfalls should be taken into account in the operating theatre. In this narrative review, we discuss characteristics of types of diabetes other than type 2 diabetes relevant to the anaesthetist, based on available literature and data from our clinic.

[Hypoglycaemia in patients without diabetes mellitus]. / Hypoglykemie bij patiënten zonder diabetes mellitus.

A structured approach in the diagnostic process of hypoglycemia is important to find the right diagnosis. The first step is to recognize the symptoms of hypoglycemia, confirming the hypoglycemia during symptoms and dissolvement of complaints once the glucose level is restored to normal. This confirms the Whipple triad. The second step is to exclude common causes. The third, and most important, step is a diagnostic fasting test. Measurement of insulin and C-peptide during hypoglycemia will guide to exogenic or endogenic causes of hyperinsulinism. Targeted additional investigation is then required. Often the underlying cause is treatable. This justifies the need to measure a well-timed serum glucose when hypoglycemia is suspected to make a quick diagnosis.

Preclinical Autoimmune Disease: a Comparison of Rheumatoid Arthritis, Systemic Lupus Erythematosus, Multiple Sclerosis and Type 1 Diabetes.

The preclinical phase of autoimmune disorders is characterized by an initial asymptomatic phase of varying length followed by nonspecific signs and symptoms. A variety of autoimmune and inflammatory manifestations can be present and tend to increase in the last months to years before a clinical diagnosis can be made. The phenotype of an autoimmune disease depends on the involved organs, the underlying genetic susceptibility and pathophysiological processes. There are different as well as shared genetic or environmental risk factors and pathophysiological mechanisms between separate diseases. To shed more light on this, in this narrative review we compare the preclinical disease course of four important autoimmune diseases with distinct phenotypes: rheumatoid arthritis (RA), Systemic Lupus Erythematosus (SLE), multiple sclerosis (MS) and type 1 diabetes (T1D). In general, we observed some notable similarities such as a North-South gradient of decreasing prevalence, a female preponderance (except for T1D), major genetic risk factors at the HLA level, partly overlapping cytokine profiles and lifestyle risk factors such as obesity, smoking and stress. The latter risk factors are known to produce a state of chronic systemic low grade inflammation. A central characteristic of all four diseases is an on average lengthy prodromal phase with no or minor symptoms which can last many years, suggesting a gradually evolving interaction between the genetic profile and the environment. Part of the abnormalities may be present in unaffected family members, and autoimmune diseases can also cluster in families. In conclusion, a promising strategy for prevention of autoimmune diseases might be to address adverse life style factors by public health measures at the population level.

Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum: A prospective cohort study.

INTRODUCTION: Little is known about the pathophysiology of hyperemesis gravidarum (HG). Proposed underlying causes are multifactorial and thyroid function is hypothesized to be causally involved. In this study, we aimed to assess the utility of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) as a marker and predictor for the severity and clinical course of HG. MATERIAL AND METHODS: We conducted a prospective cohort study including women admitted for HG between 5 and 20 weeks of gestation in 19 hospitals in the Netherlands. Women with a medical history of thyroid disease were excluded. TSH and FT4 were measured at study entry. To adjust for gestational age, we calculated TSH multiples of the median (MoM). We assessed HG severity at study entry as severity of nausea and vomiting (by the Pregnancy Unique Quantification of Emesis and nausea score), weight change compared with prepregnancy weight, and quality of life. We assessed the clinical course of HG as severity of nausea and vomiting and quality of life 1 week after inclusion, duration of hospital admissions, and readmissions. We performed multivariable regression analysis with absolute TSH, TSH MoMs, and FT4. RESULTS: Between 2013 and 2016, 215 women participated in the cohort. TSH, TSH MoM, and FT4 were available for, respectively, 150, 126, and 106 of these women. Multivariable linear regression analysis showed that lower TSH MoM was significantly associated with increased weight loss or lower weight gain at study entry (ΔKg; ß = 2.00, 95% CI 0.47-3.53), whereas absolute TSH and FT4 were not. Lower TSH, not lower TSH MoM or FT4, was significantly associated with lower nausea and vomiting scores 1 week after inclusion (ß = 1.74, 95% CI 0.36-3.11). TSH and FT4 showed no association with any of the other markers of the severity or clinical course of HG. Twenty-one out of 215 (9.8%) women had gestational transient thyrotoxicosis. Women with gestational transient thyrotoxicosis had a lower quality of life 1 week after inclusion than women with no gestational transient thyrotoxicosis (p = 0.03). CONCLUSIONS: Our findings show an inconsistent role for TSH, TSH MoM, or FT4 at time of admission and provide little guidance on the severity and clinical course of HG.

Sex differences in cardiometabolic risk factors, pharmacological treatment and risk factor control in type 2 diabetes: findings from the Dutch Diabetes Pearl cohort.

INTRODUCTION: Sex differences in cardiometabolic risk factors and their management in type 2 diabetes (T2D) have not been fully identified. Therefore, we aimed to examine differences in cardiometabolic risk factor levels, pharmacological treatment and achievement of risk factor control between women and men with T2D. RESEARCH DESIGN AND METHODS: Cross-sectional data from the Dutch Diabetes Pearl cohort were used (n=6637, 40% women). Linear and Poisson regression analyses were used to examine sex differences in cardiometabolic risk factor levels, treatment, and control. RESULTS: Compared with men, women had a significantly higher body mass index (BMI) (mean difference 1.79 kg/m2 (95% CI 1.49 to 2.08)), while no differences were found in hemoglobin A1c (HbA1c) and systolic blood pressure (SBP). Women had lower diastolic blood pressure (-1.94 mm Hg (95% CI -2.44 to -1.43)), higher total cholesterol (TC) (0.44 mmol/L (95% CI 0.38 to 0.51)), low-density lipoprotein cholesterol (LDL-c) (0.26 mmol/L (95% CI 0.22 to 0.31)), and high-density lipoprotein cholesterol (HDL-c) sex-standardized (0.02 mmol/L (95% CI 0.00 to 0.04)), and lower TC:HDL ratio (-0.29 (95% CI -0.36 to -0.23)) and triglycerides (geometric mean ratio 0.91 (95% CI 0.85 to 0.98)). Women had a 16% higher probability of being treated with antihypertensive medication in the presence of high cardiovascular disease (CVD) risk and elevated SBP than men (relative risk 0.84 (95% CI 0.73 to 0.98)), whereas no sex differences were found for glucose-lowering medication and lipid-modifying medication. Among those treated, women were less likely to achieve treatment targets of HbA1c (0.92 (95% CI 0.87 to 0.98)) and LDL-c (0.89 (95% CI 0.85 to 0.92)) than men, while no differences for SBP were found. CONCLUSIONS: In this Dutch T2D population, women had a slightly different cardiometabolic risk profile compared with men and a substantially higher BMI. Women had a higher probability of being treated with antihypertensive medication in the presence of high CVD risk and elevated SBP than men, and were less likely than men to achieve treatment targets for HbA1c and LDL levels.

A case report of myocardial infarction with non-obstructive coronary artery disease: Graves' disease-induced coronary artery vasospasm.

BACKGROUND: Coronary artery spasm can occur either in response to drugs or toxins. This response may result in hyper-reactivity of vascular smooth muscles or may occur spontaneously as a result of disorders in the coronary vasomotor tone. Hyperthyroidism is associated with coronary artery spasm. CASE SUMMARY: A 49-year-old female patient with a 2-day history of intermittent chest pain and electrocardiographic evidence of myocardial ischaemia was referred for emergency coronary angiography. This revealed severe right coronary artery (RCA) and left main (LM) coronary artery ostial vasospasm, both subsequently relieved with administration of multiple doses intracoronary nitroglycerine. Intravascular optical coherence tomography showed absence of atherosclerosis and no evidence of thrombus or dissection confirming the diagnosis of coronary artery vasospasm. Laboratory tests of the thyroid function were performed immediately after coronary angiography revealing Graves' disease as the cause of vasospasm. DISCUSSION: Our case represents a rare presentation of Graves' disease-induced RCA and LM coronary artery ostial vasospasm. In patients with coronary artery vasospasm thyroid function study should be mandatory, especially in young female patients.

The role of glucagon-like peptide-1 in reproduction: from physiology to therapeutic perspective.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) have become firmly established in the treatment of type 2 diabetes and obesity, disorders frequently associated with diminished reproductive health. Understanding of the role of GLP-1 and GLP-1 RAs in reproduction is currently limited and largely unaddressed in clinical studies. OBJECTIVE AND RATIONALE: The purpose of this narrative review is to provide a comprehensive overview of the role of GLP-1 in reproduction and to address a therapeutic perspective that can be derived from these findings. SEARCH METHODS: We performed a series of PubMed database systemic searches, last updated on 1 February 2019, supplemented by the authors' knowledge and research experience in the field. A search algorithm was developed incorporating the terms glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor, GLP-1R, or incretins, and this was combined with terms related to reproductive health. The PICO (Population, Intervention, Comparison, Outcome) framework was used to identify interventional studies including GLP-1 RAs and dipeptidyl peptidase-4 (DPP-4) inhibitors, which prevent the degradation of endogenously released GLP-1. We identified 983 potentially relevant references. At the end of the screening process, we included 6 observational (3 preclinical and 3 human) studies, 24 interventional (9 preclinical and 15 human) studies, 4 case reports, and 1 systematic and 2 narrative reviews. OUTCOMES: The anatomical distribution of GLP-1 receptor throughout the reproductive system and observed effects of GLP-1 in preclinical models and in a few clinical studies indicate that GLP-1 might be one of the important modulating signals connecting the reproductive and metabolic system. The outcomes show that there is mostly stimulating role of GLP-1 and its mimetics in mammalian reproduction that goes beyond mere weight reduction. In addition, GLP-1 seems to have anti-inflammatory and anti-fibrotic effects in the gonads and the endometrium affected by obesity, diabetes, and polycystic ovary syndrome (PCOS). It also seems that GLP-1 RAs and DPP-4 inhibitors can reverse polycystic ovary morphology in preclinical models and decrease serum concentrations of androgens and their bioavailability in women with PCOS. Preliminary data from interventional clinical studies suggest improved menstrual regularity as well as increased fertility rates in overweight and/or obese women with PCOS treated with GLP-1 RAs in the preconception period. WIDER IMPLICATIONS: GLP-1 RAs and DPP-4 inhibitors show promise in the treatment of diabetes and obesity-related subfertility. Larger interventional studies are needed to establish the role of preconception intervention with GLP-1 based therapies, assessing fertility outcomes in obesity, PCOS, and diabetes-related fertility problems. The potential impact of the dose- and exposure time-response of different GLP-1 RAs need further exploration. Future research should also investigate sex-specific variability of GLP-1 on reproductive outcomes, in particular on the gonads where the observations in males are most conflicting.

Microcirculation and its relation to continuous subcutaneous glucose sensor accuracy in cardiac surgery patients in the intensive care unit.

OBJECTIVE: Continuous glucose monitoring could be helpful for glucose regulation in critically ill patients; however, its accuracy is uncertain and might be influenced by microcirculation. We investigated the microcirculation and its relation to the accuracy of 2 continuous glucose monitoring devices in patients after cardiac surgery. METHODS: The present prospective, observational study included 60 patients admitted for cardiac surgery. Two continuous glucose monitoring devices (Guardian Real-Time and FreeStyle Navigator) were placed before surgery. The relative absolute deviation between continuous glucose monitoring and the arterial reference glucose was calculated to assess the accuracy. Microcirculation was measured using the microvascular flow index, perfused vessel density, and proportion of perfused vessels using sublingual sidestream dark-field imaging, and tissue oxygenation using near-infrared spectroscopy. The associations were assessed using a linear mixed-effects model for repeated measures. RESULTS: The median relative absolute deviation of the Navigator was 11% (interquartile range, 8%-16%) and of the Guardian was 14% (interquartile range, 11%-18%; P = .05). Tissue oxygenation significantly increased during the intensive care unit admission (maximum 91.2% [3.9] after 6 hours) and decreased thereafter, stabilizing after 20 hours. A decrease in perfused vessel density accompanied the increase in tissue oxygenation. Microcirculatory variables were not associated with sensor accuracy. A lower peripheral temperature (Navigator, b = -0.008, P = .003; Guardian, b = -0.006, P = .048), and for the Navigator, also a higher Acute Physiology and Chronic Health Evaluation IV predicted mortality (b = 0.017, P < .001) and age (b = 0.002, P = .037) were associated with decreased sensor accuracy. CONCLUSIONS: The results of the present study have shown acceptable accuracy for both sensors in patients after cardiac surgery. The microcirculation was impaired to a limited extent compared with that in patients with sepsis and healthy controls. This impairment was not related to sensor accuracy but the peripheral temperature for both sensors and patient age and Acute Physiology and Chronic Health Evaluation IV predicted mortality for the Navigator were.