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A new minimally invasive device, while still in development, could become a lifesaver for individuals with diabetes who experience hypoglycemia, according to researchers at the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts.

In a paper published in Nature Biomedical Engineering, Siddharth R. Krishnan, PhD, now an assistant professor of electrical engineering at Stanford University in Stanford, California, and colleagues at MIT described a wireless device implanted into diabetic mice that prevented hypoglycemia.

The implant weighs < 2 g and is only 3 cm³ in size; it remains under the skin and releases a powdered version of glucagon automatically when a sensor detects low blood sugar.

The researchers simulated hypoglycemia in the mice, and the release of the dry glucagon was triggered wirelessly. Measurements showed a rapid rise in blood glucose soon after the release, with a peak of 30 mg/dL after no more than 15 minutes.

A second set of studies replicated conditions that often drive hypoglycemia, such as missed meals and automated infusions from insulin pumps. Similarly, the use of the wireless release of dry glucagon resulted in blood glucose concentrations above the threshold for hypoglycemia (average concentration of 80 mg/dL) within the first hour after the release. An area under the curve analysis over 30 minutes after release showed significant changes in the glucose group compared with the control group who received lactose.

‘A Pathway to Emergency Rescue’

“Glucagon is widely administered as an emergency rescue drug for patients suffering acute hypoglycemia, particularly in the context of type 1 diabetes,” corresponding author Daniel Anderson, PhD, a professor at the Koch Institute for Integrative Cancer Research at MIT, told Medscape Medical News.

Glucagon’s short half-life and low stability in solution has made development of pump systems a challenge, he said. By contrast, “Dry powder versions of glucagon offer long-term stability but are difficult to deliver,” he said. “An implantable device that can respond to hypoglycemia and release dry powder glucagon potentially offers a pathway to emergency rescue from hypoglycemia events without the need for patient intervention,” Anderson said.

The early impact of the dry power was unexpected, Anderson said. “The glucagon in our system is a dry powder that we designed to dissolve directly in biofluid, and the timeline for this dissolution and subsequent availability of the drug in circulation was an open question when we started this project,” he noted. “The fact that we saw biological activity within 5 minutes of drug release was an important result in this context, and not one that we predicted.”

Although the device is not ready for human use, the size and longevity are key questions for adoption in clinical practice, Anderson told Medscape Medical News. “We are working on miniaturizing the device, so it is compatible with minimally invasive insertion techniques, and with a sufficient number of doses to provide protection from acute hypoglycemia for multiple years,” he said. “So far, we have validated the device in preclinical small animal models.” Simultaneously miniaturizing the system and optimizing the dose and longevity in large animal models are the next steps for research, he added.

Unmet Need for Glycemic Control

“Hypoglycemia and fear of hypoglycemia remains major barriers to optimal glycemic control for those with diabetes,” said Andrew Kraftson, MD, a specialist in endocrinology and internal medicine at the University of Michigan, Ann Arbor, Michigan, in an interview.

“Glucagon emergency delivery devices have advanced and become more user friendly but will not work if not available or expired. Liquid glucagon presents numerous challenges and is not yet commercially available for dual hormone insulin pump use,” said Kraftson, who was not involved in the research.

“Dual hormone pumps that are being studied or have been approved in Europe are large/bulky, may require two CGM [continuous glucose monitoring] sensors, and may require glucagon to be refilled more frequently than insulin, so a nonliquid, implantable device could avoid some of the obstacles posed by liquid glucagon,” Kraftson noted.

However, more research is needed on the logistics of human implementation of the glucagon delivery device tested in the current study, Kraftson told Medscape Medical News. Questions include how the device would be implanted; how many doses the reservoir would hold; and how often, on average, it would need to be changed, he said. Other factors include how cumbersome this device might be for humans, potential risks for irritation or infection, and options for manual delivery in the event of a malfunctioning CGM or signal challenges in device communication, he said.

“Ideally, glucagon use for patients with diabetes would expand beyond emergency rescue,” Kraftson added. “Reducing or even holding insulin is sometimes insufficient to avoid hypoglycemia, particularly rapid onset.” 

“Additionally, eating carbohydrates to prevent or treat hypoglycemia is not ideal given the risk of subsequent overcorrection/hyperglycemia and weight gain; therefore, more frequent, sensor/algorithm-based use of glucagon can more effectively achieve stable glucose levels and help avoid the ‘rollercoaster,’” he said.

The small size of the device in the current study may limit its ability to participate in the larger mission of glucose management but could certainly still play an important role in hypoglycemia reduction, he noted.

This study was funded by the Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health, a JDRF postdoctoral fellowship, and the National Institute of Biomedical Imaging and Bioengineering.

Anderson and several coauthors reported being inventors on a patent application relevant to the technology described in this study but had no other financial conflicts of interest.

Kraftson had no financial conflicts to disclose.

Key Messages

• Sestrin-1 levels were significantly higher in patients with rheumatoid arthritis (RA) compared to controls, though no correlation was found between Sestrin-1 levels and RA disease activity as measured by DAS28, suggesting that Sestrin-1 may serve as a distinct biomarker in RA rather than a disease activity indicator.
• Carotid intima media thickness (cIMT) was notably elevated in the RA patient group, underscoring the heightened cardiovascular risk in RA. However, no significant correlation between cIMT and Sestrin-1 levels was observed, indicating that Sestrin-1 might independently impact RA pathology outside of cardiovascular influence.
• Decreased Sestrin-1 levels were associated with an increased risk of RA, hinting at a potential protective role for Sestrin-1 in the disease. Further molecular studies are essential to explore Sestrin-1’s mechanisms, particularly its anti-inflammatory and antioxidant properties, which may offer new therapeutic avenues in RA management.

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease and usually causes inflammation in the joints.¹ However, recent studies show that RA can affect not only the joints but also the cardiovascular system.^2,3 RA can increase the risk of atherosclerosis and therefore lead to heart diseases and cardiovascular events such as stroke.⁴ It is thought that systemic inflammation-mediated vascular damage, high cholesterol, insulin resistance, drugs such as corticosteroids in the treatment of RA, physical inactivity in RA patients, and epigenetic origins in this patient group play a role among the causes of this situation.⁵ One of the most widely used and validated tools for assessing RA disease activity is the Disease Activity Score in 28 joints (DAS-28). This composite index incorporates the number of tender joints (TJC28), the number of swollen joints (SJC28), the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level, and the patient’s global health assessment (GH). The DAS-28 score is calculated using the following formula: DAS28 = 0.56 × √(TJC28) + 0.28 × √(SJC28) + 0.70 × ln(ESR) + 0.014 × GH. Higher DAS-28 values indicate greater disease activity, and specific thresholds help classify disease status as remission, low, moderate, or high activity. This score enables clinicians to monitor treatment response and guide therapeutic decisions over time.

Sestrin-1, recognized for its role in mitigating cellular oxidative stress, functions by counteracting the deleterious impact of accumulated free radicals within cells.⁶ This protein serves to safeguard cellular health, regulate stress response mechanisms, and modulate metabolism.^7,8 Pertinent to this discussion is the conjecture that alterations in Sestrin-1 levels among individuals afflicted with rheumatoid arthritis may influence the propensity for atherosclerosis development. However, further investigations are imperative to elucidate this association comprehensively. Specifically, in-depth exploration into the precise mechanisms and consequences of Sestrin-1 involvement in the pathogenesis of conditions like rheumatoid arthritis and atherosclerosis holds paramount significance in advancing this field of study.

Methods

Compliance with Ethical Standards

The study was reviewed and approved by the institutional research ethics board (from the Ethics Committee of Necmettin Erbakan University (Approval Number: 2022/3890)), adhering to the principles of the Helsinki Declaration. Written informed consent was obtained from all participants. Artificial intelligence-supported technologies were not used in the study.

Study Population

In this investigation, 55 individuals diagnosed with rheumatoid arthritis (RA) were enrolled alongside 55 age- and gender-matched healthy controls serving as the comparison group. Exclusion criteria encompassed pregnant women, individuals under 18 years of age, those with cardiovascular conditions (including coronary artery disease, hypertension, valvular heart disease, and heart failure), thyroid disorders, diabetes, hyperlipidemia, acute or chronic renal impairment, neurological ailments (such as cerebrovascular disease and demyelinating disorders), as well as those with prior history of rheumatological and autoimmune disorders, and malignancies. Disease activity assessments, including the Disease Activity Score 28 (DAS-28) and the visual analogue scale (VAS), were utilized to measure patients’ clinical parameters. Furthermore, sociodemographic characteristics of all participants were meticulously recorded.

Laboratory Parameters

Venous blood samples of all patients were taken after 10–12 hours of fasting. Blood samples were centrifuged at 4000 rpm for 5 min and stored at −80 °C. Thawed serum samples of all individuals were studied on the day of the study. Biochemical tests were analyzed by the photometric method of the Abbott Architect C16000 analyzer. Hematological parameters were examined with an Abbott Cell Dyn Ruby analyzer. C-reactive protein (CRP) was assessed by the nephelometric method of Coulter Immage 800. The study was completed in 3 months.

Sestrin-1 and cIMT Measurements

Serum Sestrin-1 levels were analyzed by Enzyme-Linked Immunosorbent Assay (ELISA) using a commercial kit (Human Sestrin-1 CD138 ELISA Kit, Bioassay Technology Laboratory, China) according to the manufacturer’s instructions. The cIMT of all patients in the patient and control groups was measured blindly by the same cardiologist experienced in vascular imaging using a 9L4 (4.0–9.0 MHz) linear transducer with a Siemens Acuson S3000 ultrasound device. The patient’s carotid system was evaluated in B-mode, pulsed Doppler mode and color mode, with the patient in a supine position, with the neck slightly extended, and turned to the opposite direction of the side to be examined. The distance between the first echogenic line adjacent to the vessel lumen and the second echogenic line was established as a standard by measuring the intima-media thickness 3 cm proximal to the common carotid artery bifurcation level. cIMT measurements were always performed by a blinded cardiologist from the plaque-free arterial segment.

Statistical Analysis

The data obtained as a result of the research were analyzed in a computer environment with the SPSS (Statistical Package for Social Sciences) 18.0 package program. In descriptive analyses, frequency data were given using number (n) and percentage (%), and numerical data were given using mean ± standard deviation (Interquartile Range). Chi-square (x2) test and Fisher Exact test were used to compare categorical data. The suitability of numerical data for normal distribution was examined with the Kolmogorov–Smirnov test. The distribution of normally distributed numerical data in two independent groups was examined with the T test in Independent Groups, and the distribution of non-normally distributed numerical data was examined with the Mann Whitney U-test. The relationship between non-normally distributed numerical data was examined with Spearman Correlation analysis. Correlation relationships: low correlation if r=0.05–0.30, low-moderate correlation if r=0.30–0.40, moderate correlation if r=0.40–0.60, r=0, 60–0.70 was considered good correlation, r=0.70–0.75 was considered very good correlation, and r= 0.75–1.00 was considered excellent correlation. The cut-off point determination properties of the variables for the presence of Rheumatoid Arthritis were evaluated by ROC (Receiver Operating Characteristics) Curve Analysis. Binary Logistic Regression analysis was used to predict the risk of RA for variables. Propensity score matching (PSM) was not applied, as the RA and control groups were already balanced in terms of key baseline characteristics such as age and sex (p > 0.05). Additionally, due to the relatively small sample size, PSM was avoided to prevent further reduction in statistical power. The results were evaluated at the 95% confidence interval and the significance level was p<0.05.

Results

The study comprised 55 patients diagnosed with rheumatoid arthritis (RA) and 55 healthy individuals. Among the patients, 76.4% (n=42) were female. The mean age of the patient cohort was 55.93±9.30 years, ranging from 49.0 to 62.0 years. Regarding treatment, 50.9% (n=28) of RA patients were administered methotrexate, while 32.7% (n=18) were prescribed deltacortil, and an equal percentage received salazoprin therapy. The distribution of Disease Activity Score 28 (DAS-28) among patients was recorded as 2.87±1.56 (ranging from 2.0 to 3.0), while the patient-reported Visual Analogue Scale (VAS) score averaged 3.42±3.03 (ranging from 1.0 to 6.0). Additionally, the physician-assessed VAS score was determined to be 1.78±1.69 (ranging from 1.0 to 2.0) (see Table 1).

Table 2 presents the distribution of demographic characteristics, Electrocardiographic, Echocardiography, and laboratory parameters within both the patient and control cohorts. Among the Echocardiography findings, reduced right ventricular systolic movement (RVSM) and tricuspid annular plane systolic excursion (TAPSE) were observed in the patient group compared to the control group, accompanied by elevated estimated systolic pulmonary artery pressure (PAP) measurements (p<0.001). Moreover, right carotid intima media thickness (CIMT) levels were notably higher in RA patients (p = 0.036). Sestrin-1 levels exhibited a significant decrease in RA patients compared to the control group (p<0.001). In terms of laboratory parameters, platelet and creatinine levels were lower in the patient group relative to the control group, whereas urea, sodium, and potassium levels were elevated (p values; p=0.011; p=0.047; p=0.031; p=0.002; p<0.001, respectively).

Table 2 Distribution of Data According to Patient and Control Groups

ROC curve analysis was performed to determine the cut-off point of Sestrin-1 parameter in predicting RA patients. It was determined that Sestrin-1 values of 10.38 and lower could predict the diagnosis of RA with 76.4% sensitivity and 76.4% specificity. The area under the curve was determined as 0.858 (p<0.001; CI: 0.791–0.924). (Figure 1). Univariate and multivariate regression analysis results are presented in Table 3. The model created with these data was compatible. According to the results of multivariate analysis, 1 unit increase in Mitral A measurement increases the risk of RA by 1.351 times (p = 0.005); Decreasing Sestrin-1 measurement by 1 unit reduces the risk of RA by 0.633 times (p = 0.031).

Table 3 Logistic Regression Analysis for RA

Figure 1 ROC Curve for Sestrin-1.

Discussion

We observed higher Sestrin-1 levels in the RA patient group compared to the control group. However, no correlation was found between RA disease activity (DAS28) and Sestrin-1 levels. Additionally, carotid intima media thickness (cIMT) values were elevated in the RA group compared to the control group. In correlation analysis, no significant relationship was detected between cIMT values and Sestrin-1 levels. Furthermore, in multivariate regression analysis, it was noted that decreased Sestrin-1 levels increased the risk of RA.

The excessive production of pro-inflammatory cytokines such as TNF-alpha and IL-6 is known to play a pivotal role in the pathogenesis of RA.⁹ These cytokines can induce vascular damage by enhancing endothelial cell activation and influencing the formation of atherosclerotic plaques. Consequently, RA patients are predisposed to early cardiovascular disease. Carotid intima media thickness (cIMT) measurements serve as an indicator of subclinical atherosclerosis and are recognized as predictors of cardiovascular disease risk.^10–12 Studies conducted in RA patients have demonstrated an increase in cIMT, which correlates with the duration of the disease.¹³

Sestrin-1 is a protein complex that plays a crucial role in the cellular stress response.¹⁴ It exerts a protective function against oxidative stress and other harmful stimuli within cells. Moreover, Sestrin-1 is recognized for its involvement in slowing down cellular aging processes and regulating metabolism. Recent investigations have shed light on the impact of Sestrin-1 on the immune system and its potential implication in the development of autoimmune disorders.¹⁵ In a study by Sun Yunfeng et al, aerobic exercise-induced upregulation of Sestrin levels was associated with the suppression of IL-1β, IL-6, TNF-α, and NF-κB activation, thereby reducing inflammatory responses in atherosclerosis.¹⁶ The effects of Sestrin-1 on RA may operate through diverse mechanisms. For instance, its anti-inflammatory properties could contribute to mitigating the autoimmune process and alleviating RA symptoms. Additionally, the antioxidant attributes of Sestrin-1 may aid in diminishing oxidative stress, thus potentially mitigating joint damage observed in RA.

Despite these observations, further research is warranted to elucidate the precise role of Sestrin-1 in the pathogenesis of RA. This necessitates additional molecular and cellular investigations to delineate the specific mechanisms and targets associated with Sestrin-1. Furthermore, extensive clinical studies are imperative to ascertain the clinical efficacy and safety profile of Sestrin-1 utilization in RA treatment.

Conclusion

Rheumatoid arthritis represents a multifaceted autoimmune condition influenced by numerous factors in its pathogenesis. Our study presents pioneering evidence suggesting a potential involvement of Sestrin-1 in rheumatoid arthritis. Nevertheless, elucidating the precise nature of this relationship and delineating the potential therapeutic role of Sestrin-1 in treating rheumatoid arthritis necessitates further investigation.

Author Contributions

All authors have made substantive contributions to the study, and all authors endorse the data and conclusions. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The authors have no commercial associations or sources of support that might pose a conflict of interest.

Disclosure

This paper has been uploaded to ResearchGate as a preprint: https://www.researchgate.net/publication/380558429_Levels_of_Sestrin1_in_Rheumatoid_Arthritis_Patients_Exploring_the_Association_with_Atherosclerosis. The authors report no conflicts of interest in this work.

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