Protocol of a Prospective Observational Study on the Relationship Between Glucose Fluctuation and Cardiovascular Events in Patients with Type 2 Diabetes

IntroductionA recent study demonstrated that large glucose fluctuations were associated with an increased incidence of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) and acute myocardial infarction. However, it is unknown whether glucose fluctuations are related to the incidence of CVD or the progression of atherosclerosis in patients with T2DM with no apparent history of CVD. In this protocol, we will be investigating the relationships of glucose fluctuations evaluated by continuous glucose monitoring (CGM) to the incidence of composite cardiovascular events and the progression of atherosclerosis in patients with T2DM who had no apparent history of CVD.MethodsThis is a prospective, multicenter, 5-year follow-up observational study. Between April 2018 and October 2019, 1000 participants are expected to be recruited at 34 medical institutions. CGM using FreeStyle Libre Pro is useful for evaluating glucose fluctuations by continuously monitoring glucose levels in interstitial fluid for up to 14 days. The primary study outcome is the relationship between fluctuations in glucose levels evaluated by CGM and the incidence of composite cardiovascular events. Secondary outcomes include the relationships of fluctuations in glucose levels evaluated by CGM to changes in carotid intima media thickness evaluated by echography or grayscale median (an index of tissue characteristics of the carotid wall), brachial–ankle pulse wave velocity, development or progression of diabetic retinopathy or nephropathy, quality-of-life-related diabetes therapy, quality of sleep, development of dementia, and autonomic nerve function.Planned OutcomeThis protocol is designed to investigate the relationship between glucose fluctuations and the incidence of composite cardiovascular events. We completed the registration of 1000 participants in March 2019. Thus, results will be available in 2024. We expect that evaluating glucose fluctuations will aid the identification of patients with a high probability of developing CVD.Trial RegistrationClinicalTrials.gov identifier, UMIN000032325

Angiotensin II inhibition: a potential treatment to slow the progression of sarcopenia

Sarcopenia is defined as the progressive and generalized loss of skeletal muscle mass and strength, which is associated with increased likelihood of adverse outcomes including falls, fractures, physical disability, and mortality. The etiology of sarcopenia has been postulated to be multifactorial with genetics, aging, immobility, nutritional deficiencies, inflammation, stress, and endocrine factors all contributing to the imbalance of muscle anabolism and catabolism. The prevalence of sarcopenia is estimated to range from 13 to 24% in adults over 60 years of age and up to 50% in persons aged 80 and older. As the population continues to age, the prevalence of sarcopenia continues to increase and is expected to affect 500 million people by the year 2050. Sarcopenia impacts the overall health of patients through limitations in functional status, increase in hospital readmissions, poorer hospital outcomes, and increase in overall mortality. Thus, there exists a need to prevent or reduce the occurrence of sarcopenia. Here, we explore the potential mechanisms and current studies regarding angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors on reducing the development of sarcopenia through the associated changes in cardiovascular function, renal function, muscle fiber composition, inflammation, endothelial dysfunction, metabolic efficiency, and mitochondrial function

Relationship between fluctuations in glucose levels measured by continuous glucose monitoring and vascular endothelial dysfunction in type 2 diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>Fluctuations in blood glucose level cause endothelial dysfunction and play a critical role in onset and/or progression of atherosclerosis. We hypothesized that fluctuation in blood glucose levels correlate with vascular endothelial dysfunction and that this relationship can be assessed using common bedside medical devices.</p> <p>Methods</p> <p>Fluctuations in blood glucose levels were measured over 24 hours by continuous glucose monitoring (CGM) on admission day 2 in 57 patients with type 2 diabetes mellitus. The reactive hyperemia index (RHI), an index of vascular endothelial function, was measured using peripheral arterial tonometry (EndoPAT) on admission day 3.</p> <p>Results</p> <p>The natural logarithmic-scaled RHI (L_RHI) correlated with SD (r=−0.504; <it>P</it><0.001), the mean amplitude of glycemic excursions (MAGE) (r=−0.571; <it>P</it><0.001), mean postprandial glucose excursion (MPPGE) (r=−0.411; <it>P</it>=0.001) and percentage of time ≥200 mg/dl (r=−0.292; <it>P</it>=0.028). In 12 patients with hypoglycemia, L_RHI also correlated with the percentage of time at hypoglycemia (r=−0.589; <it>P=</it>0.044). L_RHI did not correlate with HbA1c or fasting plasma glucose levels. Furthermore, L_RHI did not correlate with LDL cholesterol, HDL cholesterol, and triglyceride levels or with systolic and diastolic blood pressures. Finally, multivariate analysis identified MAGE as the only significant determinant of L_RHI.</p> <p>Conclusions</p> <p>Fluctuations in blood glucose levels play a significant role in vascular endothelial dysfunction in type 2 diabetes.</p> <p>Trial registration</p> <p>UMIN000007581</p

Early effects of sodium-glucose co-transporter 2 inhibitors in type 2 diabetes: study based on continuous glucose monitoring

Abstract Background Inhibitors of sodium-glucose co-transporter 2 (SGLT2) have immediate glucose-lowering effects by promoting urinary glucose excretion, without altering insulin level. Only a few studies have evaluated blood glucose dynamics in the early period after administration. The present retrospective study was designed to determine the immediate effects of SGLT2 inhibitors on blood glucose dynamics. Methods The study subjects were 24 patients with type 2 diabetes whose blood glucose dynamics were evaluated with continuous glucose monitoring for 1 week before and after initiation of SGLT2 inhibitor therapy. Blood glucose dynamics were examined on days −1, 0 (treatment commencement day), 3, and 7 by evaluating different continuous glucose monitoring parameters and blood glucose before each meal. Furthermore, blood glucose levels at 1 and 2 h after each meal and daily urinary glucose levels were determined. Results A significant reduction in blood glucose levels 2 h after breakfast was observed between the day before treatment (249.8 mg/dL) and the day treatment started (218.9 mg/dL). The mean daily blood glucose level improved significantly from 201.4 to 142.3 mg/dL from the day the treatment started. Blood glucose variation also improved significantly by week 1, as demonstrated by changes in standard deviation and mean amplitude of glycemic excursions (from 39.6 to 31.7 and 106.9 to 87.4 mg/dL, respectively). The percent time at blood glucose <70 mg/dL remained unchanged while urinary glucose on day 7 correlated with minimum blood glucose level (r = 0.474, p = 0.022). Conclusions The results showed that the SGLT2 inhibitors lower blood glucose from 2 h after the first dose and improve blood glucose variation by week 1 after start of the treatment. Furthermore, SGLT2 inhibitors did not alter the incidence of hypoglycemic episodes at week 1, suggesting that SGLT2 protects against severe hypoglycemia by inhibiting urinary glucose excretion

Endoplasmic Reticulum Chemical Chaperone 3-Hydroxy-2-Naphthoic Acid Reduces Angiotensin II-Induced Vascular Remodeling and Hypertension In Vivo and Protein Synthesis In Vitro

Background Investigations into alternative treatments for hypertension are necessary because current treatments cannot fully reduce the risk for the development of cardiovascular diseases. Chronic activation of unfolded protein response attributable to the endoplasmic reticulum stress has been proposed as a potential therapeutic target for hypertension and associated vascular remodeling. Triggered by the accumulation of misfolded proteins, chronic unfolded protein response leads to downstream signaling of cellular inflammation and dysfunction. Here, we have tested our hypothesis that a novel chemical chaperone, 3-hydroxy-2-naphthoic acid (3HNA) can attenuate angiotensin II (AngII)-induced vascular remodeling and hypertension. Methods and Results Mice were infused with AngII for 2 weeks to induce vascular remodeling and hypertension with or without 3HNA treatment. We found that injections of 3HNA prevented hypertension and increase in heart weight body weight ratio induced by AngII infusion. Histological assessment revealed that 3HNA treatment prevented vascular medial thickening as well as perivascular fibrosis in response to AngII infusion. In cultured vascular smooth muscle cells, 3HNA attenuated enhancement in protein synthesis induced by AngII. In vascular adventitial fibroblasts, 3HNA prevented induction of unfolded protein response markers. Conclusions We present evidence that a chemical chaperone 3HNA prevents vascular remodeling and hypertension in mice with AngII infusion, and 3HNA further prevents increase in protein synthesis in AngII-stimulated vascular smooth muscle cells. Using 3HNA may represent a novel therapy for hypertension with multiple benefits by preserving protein homeostasis under cardiovascular stress