MicroRNAs as Biomarkers for Coronary Artery Disease Related to Type 2 Diabetes Mellitus-From Pathogenesis to Potential Clinical Application.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with still growing incidence among adults and young people worldwide. Patients with T2DM are more susceptible to developing coronary artery disease (CAD) than non-diabetic individuals. The currently used diagnostic methods do not ensure the detection of CAD at an early stage. Thus, extensive research on non-invasive, blood-based biomarkers is necessary to avoid life-threatening events. MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that are stable in human body fluids and easily detectable. A number of reports have highlighted that the aberrant expression of miRNAs may impair the diversity of signaling pathways underlying the pathophysiology of atherosclerosis, which is a key player linking T2DM with CAD. The preclinical evidence suggests the atheroprotective and atherogenic influence of miRNAs on every step of T2DM-induced atherogenesis, including endothelial dysfunction, endothelial to mesenchymal transition, macrophage activation, vascular smooth muscle cells proliferation/migration, platelet hyperactivity, and calcification. Among the 122 analyzed miRNAs, 14 top miRNAs appear to be the most consistently dysregulated in T2DM and CAD, whereas 10 miRNAs are altered in T2DM, CAD, and T2DM-CAD patients. This up-to-date overview aims to discuss the role of miRNAs in the development of diabetic CAD, emphasizing their potential clinical usefulness as novel, non-invasive biomarkers and therapeutic targets for T2DM individuals with a predisposition to undergo CAD.

Efficacy and safety of an expanded dulaglutide dose range: A phase 2, placebo-controlled trial in patients with type 2 diabetes using metformin.

AIMS: Dulaglutide, a once weekly GLP-1 receptor agonist, is approved at two doses (1.5 and 0.75 mg) for treatment of type 2 diabetes (T2D). Two higher doses of dulaglutide (3.0 and 4.5 mg) were evaluated for safety and efficacy to determine whether these doses warrant further study for improved control of glucose and body weight. MATERIALS AND METHODS: This 18-week, double-blind, phase 2 trial randomized 318 patients with T2D using ≥1500 mg metformin, to receive subcutaneous injection of placebo (n = 82), dulaglutide 1.5 mg (n = 81), dulaglutide 3.0 mg (n = 79) or dulaglutide 4.5 mg (n = 76). The primary objective was superiority of dulaglutide doses over placebo in reduction of HbA1c at 18 weeks. Secondary objectives included superiority of dulaglutide over placebo in change from baseline in body weight and fasting serum glucose (FSG) at 18 weeks. Investigational doses of dulaglutide were compared to the 1.5 mg dose as an exploratory objective. RESULTS: HbA1c reduction at 18 weeks was significantly greater with dulaglutide vs placebo (placebo, -0.44% ± 0.10% [-4.8 ± 1.1 mmol/mol]; dulaglutide 1.5 mg, -1.23% ± 0.10% [-13.5 ± 1.1 mmol/mol]; dulaglutide 3.0 mg, -1.31% ± 0.10% [-14.3 ± 1.1 mmol/mol]; dulaglutide 4.5 mg, -1.40% ± 0.10% [-15.3 ± 1.1 mmol/mol]; P < 0.001, each dose), as were changes in body weight (placebo, -1.6 ± 0.39 kg; dulaglutide 1.5 mg, -2.8 ± 0.39 kg; dulaglutide 3.0 mg, -3.9 ± 0.39 kg; dulaglutide 4.5 mg, -4.1 ± 0.41 kg; P < 0.001, each dose). All three dulaglutide doses significantly reduced FSG from baseline (1.5 mg, -36.2 ± 4.7 mg/dL [-2.0 ± 0.3 mmol/L]; 3.0 mg, -34.5 ± 4.5 mg/dL [-1.9 ± 0.3 mmol/L]; 4.5 mg, -38.0 ± 4.7 mg/dL [-2.1 ± 0.3 mmol/L]) vs placebo (-12.4 ± 4.5 mg/dL [-0.7 ± 0.3 mmol/L]) (P < 0.001, all). Safety profiles of the higher doses were consistent with the established safety profile for dulaglutide. Gastrointestinal events were mostly mild to moderate, and was dose-related for nausea. CONCLUSION: All three dulaglutide doses were superior to placebo in improving glycaemic control and reducing body weight in participants with T2D using metformin. The potential for doses of dulaglutide of 3.0 and 4.5 mg to provide additional glycaemic benefit and weight reduction with an acceptable safety profile, compared with the 1.5 mg dose, warrants further study in a phase 3 trial.

Toll-Like Receptors-2 and -4 in Graves' Disease-Key Players or Bystanders?

Graves' disease (GD) is an autoimmune disease that affects the thyroid. The development of autoimmunity is associated with innate immune responses where the prominent role plays Toll-like receptors (TLRs). The aim of our study was to assess the relationship between the expression levels of TLR-2 and TLR-4 on CD4+ and CD8+ T as well as CD19+ B lymphocytes in patients with GD and selected clinical parameters. The study group consisted of 32 women with GD, the control group consisted of 20 healthy women. Immunophenotyping was performed using the flow cytometry and cytokines concentrations were assessed using ELISA assay. The mean percentage of CD4+/TLR-2+ and CD8+/TLR-2+ T cells in patients with GD was higher than in the control group (p < 0.0001). After obtaining euthyroidism, the mean percentage of CD4+/TLR-2+ T cells in patients with GD decreased (p < 0.0001). The expression level of TLR-2 on CD4+ T lymphocytes correlated with serum FT3 concentration in patients with GD (r = 0.47, p = 0.007). The mean percentage of CD8+/TLR-2+ T cells in patients with GD before treatment compared to patients with GD after obtaining euthyroidism was higher (p = 0.0163). Similar findings were found for TLR-4. Thus the TLR-2 and TLR-4 can be a prognostic marker for Graves' disease.

Does the Epstein-Barr Virus Play a Role in the Pathogenesis of Graves' Disease?

Graves' disease (GD) it the most common chronic organ-specific thyroid disorder without a fully recognized etiology. The pathogenesis of the disease accounts for an interaction between genetic, environmental, and immunological factors. The most important environmental factors include viral and bacterial infections. The Epstein-Barr virus (EBV) is one of the most common latent human viruses. Literature has suggested its role in the development of certain allergic and autoimmune diseases. EBV also exhibits oncogenic properties. The aim of the study was to analyze and compare the presence of EBV DNA in peripheral blood mononuclear cells (PBMCs) in patients with newly recognized GD and to find a correlation between EBV infection and the clinical picture of GD. The study included 39 untreated patients with newly diagnosed GD and a control group of 20 healthy volunteers who were gender and age matched. EBV DNA was detected with reverse transcription polymerase chain reaction (RT PCR) assay. The studies showed a significantly higher incidence of EBV copies in PBMCs among GD patients compared to the control group. Whereas, no significant correlations were found between the incidence of EBV copies and the evaluated clinical parameters. Our results suggest a probable role of EBV in GD development. EBV infection does not affect the clinical picture of Graves' disease.

Gestational diabetes mellitus - literature review on selected cytokines and hormones of confirmed or possible role in its pathogenesis.

The incidence of gestational diabetes mellitus (GDM) increases globally, including Poland. Considering serious consequences of gestational diabetes for both mother and fetus, screening for this disorder is an obligatory element of managing pregnant woman. The pathogenesis of gestational diabetes is not yet thoroughly explained. However, it is insulin resistance and chronic subclinical inflammatory process which are considered to be major factors responsible for the development of GDM. These two states are triggered mainly by secretion of proinflammatory cytokines and by abnormal function of adipose tissue. The study reviews the literature on selected hormones and cytokines whose role in the GDM pathogenesis has been already confirmed as well as on those proteins whose role is either not yet fully understood or which may possibly participate in GDM development. Owing to the fact that underlying mechanisms of GDM are, in general, similar to the mechanisms responsible for metabolic disorders such as diabetes mellitus type 2 or obesity, in this review we focus first on the role these molecules play in pathogenesis of metabolic disorders and then present current state of knowledge on their action in gestational diabetes development. The review presents: TNF alpha, adipokines - adiponectin and leptin and relatively newly discovered proteins: fetuin A, periostin, angiopoietin-like protein 8 or high mobility group box.

Perioperative complications of gynecologic surgery in diabetic patients.

OBJECTIVES: The aim of the study was to estimate whether diabetes was an independent risk factor for perioperative complications in patients undergoing gynecologic surgery. MATERIAL AND METHODS: The study population consisted of 182 women (diabetics and controls) who underwent elective gynecologic surgery. Each patient without diabetes from the control group and matched for age and body mass index diabetic patient were admitted with the same gynecologic diagnosis, underwent the same gynecologic procedure, were operated on in the same operating room and were hospitalized within the same time interval. The following parameters of the perioperative period were compared between every matched pair of patients (diabetic vs. non-diabetic patient): number and characteristics of intra- and postoperative complications, length of postoperative hospitalization, decrease in hemoglobin level, increase in body temperature, and postoperative use of antibiotics. RESULTS: The study revealed no statistically significant differences between the diabetic patients and pair-matched controls in terms of the examined parameters of the perioperative period. CONCLUSIONS: Diabetes was not an independent risk factor for early postoperative complications after gynecologic procedures in the examined population. Good pre-operative glycemic control and strict cooperation of the diabetologist with the surgeon in the perioperative period resulted in reduction of the complication rate to the level typical for non-diabetic patients.

Clinical implications of vitamin D deficiency.

Vitamin D deficiency is a common medical problem worldwide and its prevalence rises along with latitude, obesity, sedentary lifestyle, limited sunlight exposure and aging. A great body of evidence has shown that patients with vitamin D deficiency have increased cardiovascular risks and total mortality. Conversely, the presence of comorbidities progressive with age such as abdominal obesity, insulin resistance, type 2 diabetes and hypertension places the patients at an increased risk of vitamin D deficiency. The multidirectional effect of vitamin D deficiency is present in different phases of the aging process. Based on the literature review, the risk factors for vitamin D insufficiency most often found in post-menopausal women include limited sun exposure and time spent outdoors, inadequate dietary vitamin D intake, winter season and increased age. Vitamin D supplementation in this group might offer prevention of falls and fractures and may be beneficial for cardiovascular health, what may be especially important in osteoporotic and elderly populations. Prevention and treatment processes involve education regarding sunlight exposure and pharmacological cholecalciferol supplementation according to the recommendations for Central Europe. This manuscript reviews the role of vitamin D and its deficiency and considers their clinical implications, with particular regard to peri- and postmenopausal women.

Polycystic ovary syndrome: clinical implication in perimenopause.

Polycystic ovary syndrome (PCOS), a hyperandrogenic disorder, is the commonest endocrinopathy in premenopausal women. This syndrome is associated with fertility problems, clinical manifestations of hyperandrogenism and metabolic disturbances, particularly insulin resistance and obesity. There is a great body of evidence that patients with PCOS present multiple cardiovascular risk factors and cluster components of metabolic syndrome from early ages. The presence of comorbidities such as abdominal obesity, insulin resistance, type 2 diabetes, hypertension places these females at an increased risk of future cardiovascular events. However, the extent to which PCOS components are present in perimenopausal women and the degree to which PCOS increases various risk factors in addition to the known risk of the perimenopausal period have not been fully determined. The perimenopausal period per se is associated with weight gain and an increased cardiovascular risk, which may be additionally aggravated by the presence of metabolic disturbances connected with PCOS. The phenotype of PCOS may improve with aging and it is still uncertain whether the presence of PCOS significantly increases the cardiovascular risk later in women's life. Most recent data suggest that the prevalence of cardiovascular diseases and the related long-term consequences in females with PCOS seem to be lower than expected. This manuscript reviews long-term consequences of PCOS and considers their clinical implications in perimenopause.

Obesity - Standards, trends and advances.

Obesity continues to be a significant global health concern, giving rise to various complications. This review article explores the current standards and emerging innovations in diagnosing and treating obesity, including recent disease name change, staging system or therapeutic goals. This narrative review has been based on recent scientific articles from PubMed database, limiting the scope of topics to current standards and upcoming developments and breakthroughs in the diagnosis and treatment of obesity. The educational and informative nature of the review has been maintained in order to make the information presented accessible to both researchers and clinical practitioners. The recognition of diverse obesity phenotypes has prompted a paradigm shift towards a complex and patient-centered approach to diagnosis and therapy. Pharmacotherapy for obesity is evolving rapidly, with ongoing research focusing on novel molecular targets and metabolic pathways. Promising developments include dual or triple incretin analogs, oral incretin drugs, neurotransmitter-based therapies, muscle mass-increasing treatments, and therapies targeting visceral adipose tissue browning. Despite current evidence-based international standards, the field of obesity diagnosis and treatment continues to expand, with new diagnostic tools and pharmacotherapies potentially replacing current practices. Therapeutic management should be tailored to individual patients, considering obesity phenotype, health status, lifestyle, and preferences. Looking ahead, the future holds promising opportunities for obesity management, but further research is required to assess the efficacy and safety of emerging therapies. A multifactorial and personalized approach will be pivotal in addressing the diverse challenges posed by obesity.

Assessment of real-world usage of lanreotide AUTOGEL 120 in Polish acromegalic patients - results from the prospective 12-month phase of Lanro-Study.

AIM OF THE STUDY: To assess resource utilization and costs of treatment with lanreotide AUTOGEL 120 mg (ATG120) administered as part of routine acromegaly care in Poland. MATERIAL AND METHODS: A multicentre, non-interventional, observational study on resource utilization in Polish acromegalic patients treated with ATG120 at 4 weeks or extended (> 4 weeks) dosing interval. The study recruited adult acromegalic patients treated medically for ≥ 1 year including at least 3 injections of ATG120. Data on dosing interval, aspects of administration, and resource utilization were collected prospectively during 12 months. Costs were calculated in PLN from the public health-care payer perspective for the year 2013. RESULTS: 139 patients were included in the analysis. Changes in dosing regimen were reported in 14 (9.4%) patients. Combined treatment was used in 11 (8%) patients. Seventy patients (50%) received ATG120 at an extended dosing interval; the mean number of days between injections was 35.56 (SD 8.4). ATG120 was predominantly administered in an out-patient setting (77%), by health-care professionals (94%). Mean time needed for preparation and administration was 4.33 and 1.58 min, respectively, mean product wastage - 0.13 mg. Patients were predominantly treated in an out-patient setting with 7.06 physician visits/patient/year. The most common control examinations were magnetic resonance imaging of brain and brain stem (1.36/patient/year), ultrasound of the neck (1.35/patient/year), GH (1.69/patient/year), glycaemia (1.12/patient/year), IGF-1 (0.84/patient/year), pituitary-thyroid axis hormone levels assessment (TSH-0.58/patient/year, T4-0.78/patient/year). There were 0.43 hospitalizations/patient/year. For direct medical costs estimated at PLN 50 692/patient/year the main item was the costs of ATG120 (PLN 4103.87/patient/month; 97%). The mean medical cost, excluding pharmacotherapy, was PLN 1445/patient/year (out-patient care - 49%, hospitalization - 23%, diagnostics/laboratory tests - 28%). CONCLUSIONS: These results represent the current use of ATG120 in the population of Polish acromegalic patients in a realistic clinical setting. Findings that 50% of patients could be treated with dose intervals of longer than 28 days support the potential of ATG120 to reduce the treatment burden.

Diagnosis and Non-Invasive Treatment of Obesity in Adults with Type 2 Diabetes Mellitus: A Review of Guidelines.

Obesity, a chronic disease with multifactorial etiopathogenesis, is characterized by excessive accumulation of adipose tissue. Obesity prevalence is growing globally at an alarming rate. The overwhelming majority of obesity cases are caused by inappropriate lifestyles, such as overconsumption of food and inadequate physical activity. Metabolic and biochemical changes due to increased adiposity resulted in numerous comorbidities, increased all-cause mortality, and reduced quality of life. T2DM (type 2 diabetes mellitus) and obesity have many common pathogenetic points and drive each other in a vicious cycle. The aim of this article is to review obesity management guidelines and highlight the most important points. Management of both obesity-related and T2DM complications incur enormous expenses on healthcare systems. It is, therefore, paramount to provide streamlined yet custom-tailored weight management in order to avoid the negative ramifications of both diseases. Efficient obesity treatment leads to better diabetes control since some antidiabetic medications support weight reduction. Obesity treatment should be overseen by a multi-disciplinary team providing indispensable information and individually tailored regimens to patients. Weight management should be multimodal and consist chiefly of MNT (medical nutrition therapy), physical activity, and lifestyle changes. A comprehensive approach to obesity treatment may give tangible results to quality of life and comorbidities.

Obesity in perimenopause - current treatment options based on pathogenetic factors.

The health of post-menopausal women has become of paramount concern due to the aging of the world's population. Concurrently, the prevalence of obesity among postmenopausal women is expected to increase, presenting a significant public health challenge. Although weight gain during menopause is a well-observed phenomenon, its underlying causes and mechanisms remain incompletely understood. This manuscript reviews the literature to explore potential hormonal factors and pathomechanisms contributing to obesity during perimenopause, aiming to identify pathogenic factors that can guide treatment selection. Menopause-induced hormonal changes, including hypoestrogenaemia, hypergonadotropinaemia, relative hyperandrogenaemia, growth hormone deficiency, leptin resistance, and chronic stress affecting the hypothalamic-pituitary-adrenal axis, have been implicated in the onset of obesity in perimenopausal women. These hormonal fluctuations, alongside lowered daily energy expenditure, lead to metabolic alterations that elevate the risk of developing metabolic disorders and cardiovascular diseases. Weight gain in perimenopausal women is associated with higher total and abdominal adipose tissue and lower lean body mass. Addressing this issue requires individualized behavioural management, supported by effective pharmacological therapy, and, when warranted, complemented by bariatric surgery. Modern obesity treatment therapies have demonstrated safety and efficacy in clinical trials, offering the potential to reduce excess body fat, improve metabolic profiles, lower cardiovascular risk, and enhance the quality and longevity of women's lives. In addition to standard obesity therapies, the article examines different treatment strategies based on obesity's pathogenic factors, which may offer promising options for treating obesity with or without complications in perimenopausal women. One such potential approach is menopausal hormone therapy (MHT), which hypothetically targets visceral obesity by reducing visceral adipose tissue accumulation, preserving metabolically active lean body mass, and improving lipid profiles. However, despite these reported benefits, gynaecological and endocrinological societies currently do not recommend the use of MHT for obesity prevention or treatment, necessitating further research for validation. Emerging evidence suggests that visceral obesity could result from hypoestrogenaemia during perimenopause, potentially justifying the use of MHT as a causal treatment. This highlights the importance of advancing research efforts to unravel the intricate hormonal and metabolic changes that occur during perimenopause and their role in obesity development.

Clinical and Therapeutic Implications of Male Obesity.

The prevalence of obesity, a disorder linked to numerous comorbidities and metabolic complications, has recently increased dramatically worldwide and is highly prevalent in men, even at a young age. Compared to female patients, men with obesity more frequently have delayed diagnosis, higher severity of obesity, increased mortality rate, and only a minority of obese male patients are successfully treated, including with bariatric surgery. The aim of this review was to present the current state of knowledge about the clinical and therapeutic implications of obesity diagnosed in males.

Current Insights into the Potential Role of fMRI in Discovering the Mechanisms Underlying Obesity.

Obesity is becoming one of the major global health concerns. This chronic disease affects around 650 million people worldwide and is an underlying cause of a number of significant comorbidities. According to the World Health Organization (WHO) report on obesity from 2022, this disorder became the fourth leading cause of deaths in Europe. Thus, understanding the mechanisms underlying obesity is of essential importance to successfully prevent and treat this disease. The aim of this study was to review the current insights into the potential role of fMRI in discovering the mechanisms underlying obesity on the basis of recent scientific literature published up to December 2022 and searches of the PubMed, Google Scholar and Web of Science databases. The literature assessed indicated that a growing body of evidence suggests that obesity leads to changes in both structure and connectivity within the central nervous system. Emerging data from recent functional magnetic resonance imaging (fMRI) studies prove that obese individuals present an increased motivational drive to eat as well as impaired processing in reward- and control-related brain regions. Apart from this, it is clear that fMRI might be a useful tool in detection of obesity-induced changes within the central nervous system.

Basics of prevention and management of iodine-based contrast media-induced thyroid dysfunction - position paper by the Polish Society of Endocrinology.

Medical practice involves a high number of radiological examinations using iodinated contrast media (ICM). Therefore, it is crucial for doctors of different specialties to be aware of possible adverse effects associated with ICM use. The most common and well characterized adverse effect is contrast-induced nephropathy, whereas thyroidal adverse reactions remain a diagnostic and therapeutic dilemma. ICM-induced thyroid dysfunction represents a highly heterogenous group of thyroid disorders. Due to supraphysiological iodine concentration, ICM can induce both hyper- and hypothyroidism. In most cases, the ICM-induced thyroid dysfunction is oligo- or asymptomatic, mild, and transient. In rare cases, however, the ICM-induced thyroid dysfunction may be severe and life threatening. Recently, the European Thyroid Association (ETA) Guidelines for the Management of Iodine-Based Contrast Media-Induced Thyroid Dysfunction were published. The authors advise an individualized approach to prevention and treatment of ICM-induced thyroid dysfunction, based on patient's age, clinical symptoms, pre-existing thyroid diseases, coexisting morbidities, and iodine intake. There is a geographic variation of ICM-induced thyroid dysfunction prevalence, which is linked to iodine intake. The prevalence of ICM-induced hyperthyroidism, which may pose a serious therapeutic challenge, is greater in countries with iodine deficiency. Poland is a region with a history of iodine deficiency, contributing to an increased prevalence of nodular thyroid disease, especially in the elderly. Therefore, the Polish Society of Endocrinology has proposed national, simplified principles of ICM-induced thyroid dysfunction prevention and treatment.

Dopamine Agonist-Resistant Microprolactinoma-Mechanisms, Predictors and Management: A Case Report and Literature Review.

OBJECTIVE: Prolactinomas are the most common type of functional, hormone-secreting pituitary adenomas that account for about 40% of total pituitary adenomas. Typical clinical presentations include loss of menstrual periods (amenorrhea) and galactorrhoea in women and sexual dysfunction in men. Prolactinomas are preferentially treated with dopamine agonists and respond to such therapy with hormonal normalisation and tumour shrinkage. However, about 10-20% of prolactinomas are resistant to dopamine agonists. The management of dopamine agonist-resistant prolactinomas poses a therapeutic challenge and includes several possible approaches. DESIGN AND METHODS: In this study, we present a case report of a woman diagnosed with microprolactinoma at the age of 27 who did not fully respond either to treatment with dopamine agonists nor to transsphenoidal surgery. This was followed by a review of literature on the current state of knowledge about the mechanisms, predictors, and management of dopamine agonist-resistant prolactinomas on the basis of recent scientific literature published up to November 2021 and searches of the PubMed, Google Scholar, and Web of Science databases. RESULTS AND CONCLUSIONS: The exact mechanisms underlying dopamine agonists' resistance in lactotroph tumours are not fully understood, yet refractory prolactinomas pose a great challenge in everyday clinical practice. Several predictive factors that contribute to poor response to medical treatment have been identified, among them the elevated Ki-67 index. Recently, various alternative medical treatments have been considered, but their usefulness remains to be evaluated. A return of menses can serve as a first clinical indication of successful medical treatment.

Link between Insulin Resistance and Obesity-From Diagnosis to Treatment.

Insulin resistance (IR) has become a common health issue in medical practice. There are no detailed data on IR prevalence, but it is an increasing problem due to its close association with obesity. However, IR is not considered as a separate nosological entity and the diagnostic criteria are not well defined, which leads to overdiagnosis of IR and an inappropriate approach. This review aims to summarize the available literature on IR pathophysiology, its relationship with obesity, as well as diagnostic methods, clinical presentation and treatment. Excessive energy intake results in cell overload that triggers mechanisms to protect cells from further energy accumulation by reducing insulin sensitivity. Additionally, hypertrophied adipocytes and macrophage infiltration causes local inflammation that may result in general inflammation that induces IR. The clinical picture varies from skin lesions (e.g., acanthosis nigricans) to metabolic disorders such as diabetes mellitus or metabolic-associated fatty liver disease. There are numerous IR laboratory markers with varying sensitivities and specificities. Nutrition changes and regular physical activity are crucial for IR management because a reduction in adipose tissue may reverse the inflammatory state and consequently reduce the severity of insulin resistance. In cases of obesity, anti-obesity medications can be used.

Branched-chain amino acids as a novel biomarker of metabolic disturbances in women with polycystic ovary syndrome - literature review.

Polycystic ovary syndrome (PCOS) is a common, heterogeneous endocrine disorder which effects 5-10% of reproductive-age women. Recently, an association between PCOS and an increased risk of developing metabolic disturbances, such as insulin resistance, prediabetes, type 2 diabetes mellitus as well as obesity has been emphasised. Branched-chain amino acids (BCAAs), including valine (Val), leucine (Leu) and isoleucine (Ile), are a group of essential amino acids that cannot be synthesized in human body and need to be obtained from food. Several recent studies provide evidence that plasma BCAAs also serve as crucial nutrient signals and metabolic regulators. Interestingly, latest metabolomics analysis shows abnormalities in amino acid catabolism and biosynthesis in patients with PCOS, particularly in BCAAs. A growing body of evidence proves that elevated levels of BCAAs may have adverse effects on metabolic health leading to the development of insulin resistance, prediabetes, type 2 diabetes mellitus and obesity both in human and animal models. The aim of this review is to assess the current state of knowledge about the potential role of BCAAs as a novel biomarker of metabolic disturbances in women with polycystic ovary syndrome based on recent scientific literature published up to July 2021 and searches of the PubMed, Google Scholar, and Web of Science databases.

Efficacy, Safety, and Immunogenicity of Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Compared with Originator Insulin Aspart Mix 70/30 in Adults with Diabetes (GEMELLI M): A Subgroup Analysis by Prior Type of Premix Insulin.

INTRODUCTION: We compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (70% intermediate SAR341402 protamine and 30% rapid SAR341402 solution) (SARAsp-Mix) with its originator NovoMix 30 insulin aspart mix (NN-Mix) in adults with type 1 or type 2 diabetes switching from different premix insulin analogs. METHODS: This phase 3, randomized, open-label, multinational, 26-week trial (GEMELLI M) enrolled 402 participants with type 1 or type 2 diabetes. At randomization, participants switched from their prestudy premix insulin NovoMix 30 (n = 341) or Humalog Mix 25/Liprolog Mix 25 (n = 61) to equivalent (1:1) doses of either SARAsp-Mix or NN-Mix at least twice daily (1:1 randomization). In this subgroup analysis, efficacy measures [change in hemoglobin A1c (HbA1c), daily insulin dose], and safety outcomes [hypoglycemia incidence, adverse events (including hypersensitivity and injection site reactions), anti-insulin aspart antibodies] of SARAsp-Mix were compared with those of NN-Mix separately according to the participants' prestudy premix insulin. RESULTS: At week 26, change from baseline in HbA1c (primary efficacy endpoint) was similar between SARAsp-Mix and NN-Mix in those participants pretreated with NovoMix 30 [least squares (LS) mean difference 0.05%, 95% confidence interval (CI) -0.195% to 0.289%] or Humalog Mix 25/Liprolog Mix 25 (LS mean difference 0.28%, 95% CI -0.279% to 0.830%) (P value for treatment-by-subgroup interaction = 0.46). In both subgroups, safety outcomes, including immunogenicity, and changes in daily insulin doses were similar between treatments over 26 weeks. CONCLUSIONS: Efficacy, safety, and immunogenicity profiles of SARAsp-Mix are similar to NN-Mix over 26 weeks in adults with diabetes irrespective of prior type of premix insulin. TRIAL REGISTRATION: EudraCT number 2017-000092-84.

Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Versus Originator Insulin Aspart Mix 70/30 (NovoMix 30) in People with Diabetes: A 26-Week, Randomized, Open-Label Trial (GEMELLI M).

INTRODUCTION: This study compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (SARAsp-Mix) with European-approved insulin aspart mix 70/30 - NovoMix® 30 (NN-Mix) in people with type 1 (T1D) or type 2 diabetes (T2D). METHODS: This 26-week, open-label, phase 3 trial enrolled 402 people with T1D (n = 105) or T2D (n = 297) previously treated with premix insulin, who were randomized (1:1) to SARAsp-Mix (n = 204) or NN-Mix (n = 198). RESULTS: After 26 weeks, the least squares (LS) mean [median] change in HbA1c from baseline was similar in both treatment groups (SARAsp-Mix - 0.55% [- 0.60%]; NN-Mix - 0.64% [- 0.60%]). The LS mean difference for SARAsp-Mix versus NN-Mix was 0.08%, with the upper bound of the two-sided 95% confidence interval (- 0.139 to 0.303) slightly above the prespecified noninferiority margin of 0.3%. Noninferiority of SARAsp-Mix over NN-Mix was not demonstrated in the primary intent-to-treat analysis, primarily because of one extreme outlying value impacted by the COVID-19 pandemic in the SARAsp-Mix group. Noninferiority was achieved in all secondary analyses, including prespecified per-protocol supportive and COVID-19 sensitivity analyses, as well as post hoc sensitivity analyses. Other efficacy endpoints, insulin dosages, anti-insulin aspart antibody response, hypoglycemia, and adverse events were similar between groups. CONCLUSIONS: The totality of evidence indicates that SARAsp-Mix provides effective glycemic control with a similar safety and immunogenicity profile to NN-Mix in people with diabetes treated for 26 weeks. TRIAL REGISTRATION: EudraCT number 2017-000092-84.