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Glicometabolic effects on bone metabolism: from new and different pathways to new diagnostic and therapeutic aspects
Full text linkBackground
Diabetes and bone fragility are rapidly growing diseases, as osteoporosis could be defined as a complication of type 2 diabetes (T2D) (Epstein et al. 2016). Aging of populations worldwide will be responsible for an increased risk in the incidence of these two diseases. There is a pathophysiological link between the high fracture incidence and diabetes if compared with the non-diabetic state, has recently been recognized but not totally clear and understood. In fact, several mechanisms are involved in bone homeostasis by impairing the function of bone cells as osteocytes, as osteoblasts and osteoclasts, and/or modifying the structural characteristics of the bone tissue (Jiang and Xia 2018; Epstein et al. 2016). Furthermore, as osteoblasts and adipocytes both derived from the mesenchymal stem cell (MSC), their physiological differentiation could be modulated by several interacting pathways on which diabetes may shows its influence and disruption. Finally, is well known the alteration of different organs and systems during diabetic disease, involved in bone metabolism, as kidney, gut or vitamin D pathway. In fact, In the last few years, studies are focusing not only to clarify old pathways but also to discover new pathways among diabetes, obesity and bone metabolism, as Wnt signaling and the role of sclerostin, as irisin, as different formulations of vitamin D like calcidiol. Moreover, some complications derived from diabetes, as cardiac neuropathy, were not yet fully evaluated on their link to the axis diabetes-bone, leading a gap of knowledge to fill (Epstein et al. 2016; Napoli, Strollo, et al. 2014).
So, many questions remain regarding the underlying mechanisms for greater bone fragility in diabetic patients and the best approach to risk assessment and treatment to prevent fractures.
Specific aims
1) to evaluate the role of sclerostin in patients with type 2 diabetes and patients with LADA.
2) to investigate the relationship between irisin and body composition in subjects with osteoporosis and the impact of irisin levels on fragility vertebral fractures.
3) to evaluate the role of calcidiol on metabolic parameters and ß-cell function in subjects with impaired glycaemic control and insufficient vitamin D levels.
4) to evaluate the relationship between cardiac autonomic neuropathy and BMD in patients with diabetes.
Materials and Methods
1) This cross-sectional study included 98 T2D and 89 LADA patients from the Action LADA and NIRAD cohorts. Patients were further divided according to MetS status. Non-diabetic subjects (n=53) were used as controls. Serum sclerostin, bone formation (P1NP) and bone resorption (CTX) were analyzed.
2) In this cross-sectional study, 36 overweight subjects affected by at least one vertebral osteoporotic fracture confirmed by a X-ray vertebral morphometry and 36 overweight non-osteoporotic subjects were enrolled. Serum irisin levels were measured using an irisin competitive ELISA. We evaluated lumbar spine and hip BMD and body composition using dual energy X-ray absorptiometry. To measure and monitor daily physical activity, each subject wore an armband for approximately 72 hours.
3) It is a double-blind placebo-controlled clinical trial enrolling subjects with IGT, IFG and T2D (20) and 25(OH)D <20 ng/ml. In this study were enrolled a total of 150 subjects and followed up for 6 months. Subjects were either assigned (50 per group) to 1) daily supplementation of 50 mcg of calcidiol (Arm A); 2) 25 mcg of calcidiol (arm B); 3) placebo (Arm C). Fasting blood glucose and Oral Glucose Tolerance Test (OGTT), HbA1c, 25 (OH) D, calcium, phosphorus, PTH, calciuria, phosphaturia, total cholesterol, HDL cholesterol and triglycerides were measured with laboratory kits used in clinical settings. Measurements of Ox-LDL, Hs-CRP, TNF-α, IL-6, esRAGE, sRAGE were performed at the laboratory. To evaluate insulin resistance were used the ISOGTT index and the evaluation of the model of insulin-resistance homeostasis (HOMA-IR). Beta-cell function was evaluated using the insulin secretion sensitivity index-2 (ISSI-2)
4) Fourty-nine people with T2D were enrolled. Tests to determine heart rate response to deep-breathing (expiratory-to-inspiratory ratio), heart rate response to lying-to-stand test (30:15 ratio) and blood pressure response to standing were performed to detect cardiac autonomic neuropathy, and dual energy X-ray absorptiometry scan of both the lumbar spine and femoral neck were performed to evaluate bone mineral density.
Results
1) T2D subjects had higher sclerostin than LADA (p=0.0008, adjusted for sex and BMI), even when analysis was restricted to MetS subjects (adjusted p=0.03). Analyzing T2D and LADA separately, sclerostin was similar between subjects with and without MetS. However, a positive trend between sclerostin and number of MetS features was seen in T2D (p for trend=0.001) but not in LADA. Subjects with either T2D or LADA had lower CTX than controls (p=0.0003), and not significantly reduced P1NP. Sclerostin was unrelated to age or HbA1c but correlated with BMI (ρ=0.29; p=0.0001), HDL (ρ=-0.23; p=0.003), triglycerides (ρ=0.19; p=0.002) and time since diagnosis (ρ=0.32, p<0.0001).
2) No significant correlations were found between irisin and BMD at any site and between irisin with either lean or fat mass. Serum levels of irisin were not correlated with the daily physical activity. Serum irisin levels were lower in subjects with previous osteoporotic fractures than in controls (p= 0.032) and the difference in irisin levels remained significant after adjustment for creatinine (p=0.037), vitamin D (p=0.046), lean mass (p=0.02), lumbar BMD (p=0.023) and femoral BMD (p=0.032).
3) At baseline, subjects were (mean±SD) 63.8± 2.1 y.o., BMI was 27.4±1.2 kg/m2; serum glucose 115.1±8.4 mg/dL, HbA1c 6.4±0.6%, 25OHD 16.3±2.5 ng/mL. There were significant associations of 25OHD with ISOGTT (β=0.35; 95% CI, 0.14, 0.46) and β-cell function (ISSI-2; β = 0.15; 95% CI, 0.02, 0.28). At six months, 25OHD increased up to 48±3 ng/mL in Arm A (P<0.01) and to 36±5 ng/mL in Arm B (P<0.01); no significant changes in the Arm C. Subjects in Arm A had a lower risk of dysglycemia (HR= 0.85, 95% CI, 0.75-0.97 per SD increase) while no significant effects were observed in the Arms B or C. Both ISOGTT and ISSI-2 were improved in Arm A (P<0.05) while no significant changes were observed in Arm B or placebo. Serum levels of sRAGE decreased in Arm A [median 1354 (1069-1680) pg/ml (P<0.01), as compared with levels at study entry, but not in Arms B or C. No significant differences were observed for hsCRP, IL6, TNFα or lipid panel.
4) We analyzed preliminary results among two evaluations of BMD and CAN, not finding any significative difference. In fact, subjects with no CAN showed a normal BMD in 35,7% while the remaining part had osteopenia or osteoporosis (64,3%: osteopenia: 60,7%; osteoporosis: 3,6%). Evaluating BMD in subjects with CAN, 48,1 had a normal BMD while 51,9 had osteopenia (37%) or osteoporosis (14,8%).
Conclusions
1) LADA patients present lower bone resorption compared to controls, similarly to T2D. Sclerostin is increased in T2D but not in LADA suggesting possible roles on bone metabolism in T2D only.
2) The data confirm an inverse correlation between irisin levels and vertebral fragility fractures, but no significant correlation was found with BMD or lean mass. Irisin may play a protective role on bone health independent of BMD.
3) Our findings indicate that high doses of calcidiol improved indices of glucose homeostasis in prediabetic subjects and decreased circulating sRAGE levels, suggesting a positive effect also on oxidative stress.
4) No significant correlations were found evaluating BMD in subjects with T2D and CAN
Diabetes and disordered bone metabolism (diabetic osteodystrophy): time for recognition
No full textDiabetes and osteoporosis are rapidly growing diseases. The link between the high fracture incidence in diabetes as compared with the non-diabetic state has recently been recognized. While this review cannot cover every aspect of diabetic osteodystrophy, it attempts to incorporate current information from the First International Symposium on Diabetes and Bone presentations in Rome in 2014. Diabetes and osteoporosis are fast-growing diseases in the western world and are becoming a major problem in the emerging economic nations. Aging of populations worldwide will be responsible for an increased risk in the incidence of osteoporosis and diabetes. Furthermore, the economic burden due to complications of these diseases is enormous and will continue to increase unless public awareness of these diseases, the curbing of obesity, and cost-effective measures are instituted. The link between diabetes and fractures being more common in diabetics than non-diabetics has been widely recognized. At the same time, many questions remain regarding the underlying mechanisms for greater bone fragility in diabetic patients and the best approach to risk assessment and treatment to prevent fractures. Although it cannot cover every aspect of diabetic osteodystrophy, this review will attempt to incorporate current information particularly from the First International Symposium on Diabetes and Bone presentations in Rome in November 2014
Sarcopenia and osteoporosis
No full textBackground: Sarcopenia and osteoporosis are common age-related conditions that frequently coexist, forming a syndrome known as osteosarcopenia. Sarcopenia is defined by the progressive loss of muscle mass, strength, and function, while osteoporosis is characterized by reduced bone mineral density and altered bone quality. Together, they significantly increase the risk of falls, fractures, and functional decline in older adults. Summary: Osteosarcopenia arises from shared pathophysiological mechanisms, including chronic low-grade inflammation, oxidative stress, hormonal changes, and nutritional deficiencies. These factors contribute to a cycle of musculoskeletal deterioration. In addition to systemic pathways, local muscle-bone crosstalk mediated by myokines and osteokines plays a critical role. Management requires a comprehensive approach. Nutritional interventions such as adequate protein, calcium, and vitamin D intake, along with anti-inflammatory nutrients like omega-3 fatty acids and polyphenols, support musculoskeletal health. Resistance and weight-bearing exercises are essential to maintain muscle and bone mass. Pharmacological treatments for osteoporosis include bisphosphonates, denosumab, and anabolic agents, while investigational therapies for sarcopenia, such as selective androgen receptor modulators and myostatin inhibitors, offer potential benefits. Key Messages: Sarcopenia and osteoporosis share risk factors and often coexist in older adults. Early diagnosis and integrated treatment strategies are essential. Nutrition, exercise, and pharmacologic interventions can mitigate the burden of osteosarcopenia. A combined approach is more effective than treating each condition separately and may reduce falls and improve quality of life
Erectile Dysfunction Severity: The Role of Glycometabolic Compensation and Antihyperglycemic Drugs
Full text linkBackground: The aim of this study was to evaluate the prevalence of DM among patients with ED and the impact of glycometabolic compensation and antihyperglycemic treatment on ED severity. Methods: In total, 1332 patients with ED were enrolled. The diagnosis was performed through the International-Index-of-Erectile-Function questionnaire. ED severity was considered according to presence/absence of spontaneous erections, maintenance/achievement deficiency and response to PDE5-i. DM patients were clustered according to antihyperglycemic treatment: “metformin”/“insulin”/“old antihyperglycemic drugs”/“new antihyperglycemic drugs”. Results: The prevalence of DM patients was 15.8% (Group A, patients with ED and DM). Among these, the prevalence of spontaneous erections (21.0%) was lower than in the remaining patients (Group B, patients with ED without DM) (32.0%, p < 0.001). The prevalence of poor response to PDE5-i was lower in Group B (10.0%) than in Group A (35.0%, p < 0.001). Patients with good response to PDE5-i therapy showed lower HbA1c values than patients with poor/no response (6.6 ± 1.1% vs. 7.7 ± 1.9%, p = 0.02). The prevalence of absent response to PDE5-i was higher in patients treated with old antidiabetic drugs than in the population treated with new drugs (p = 0.03). Conclusion: The severity of ED and lower response to PDE5-i were higher in DM patients. A better glycometabolic profile, as well as new antihyperglycemic drugs, seem to have a positive effect on ED
Male osteoporosis: the impact of lifestyle, from nutrition to physical activity
No full textMale osteoporosis is an increasing worldwide pathological condition, characterized by an increased risk of fragility fractures, that is underestimated, underdiagnosed and undertreated. Prevention and treatment play a pivotal role in reducing fractures, and it is important to remember that therapeutic interventions include balanced nutrition and physical activity. Pharmacological treatments are the main and most effective tool to achieve numerous and decisive benefits in this population. Among these, testosterone replacement therapy, when allowed by circumstances and comorbidities, is useful. Anyway, the main goal is always to start from lifestyle, including nutrition and physical activity, plays a very important and crucial role. The many pieces of this puzzle, called lifestyle, need to be accurately collected and grouped carefully, in order to be able to have a broad picture of what needs to be integrated and what is sufficient for the ultimate purpose of enabling each individual man to have a sufficient basic health point. Thus, the purpose of this short narrative review is to highlight the preventive and therapeutic role of lifestyle components, particularly nutrition and physical activity, in males with osteoporosis. Finally, an evaluation of the impact of the main current diets used in recent years and the main physical activities as strategies for the safety of male bone health
The interlink between thyroid autoimmunity and type 1 diabetes and the impact on male and female fertility
No full text: The aim of this review is to discuss the several interconnections between thyroid autoimmunity and type 1 diabetes in terms of epidemiology, immunoserology, genetic predisposition, and pathogenic mechanisms. We will also analyze the impact of these conditions on both male and female fertility. A literature search was carried out using the MEDLINE/PubMed, Scopus, Google Scholar, ResearchGate, and Clinical Trials Registry databases with a combination of keywords. It was found that the prevalence of thyroid autoantibodies in individuals with type 1 diabetes (T1DM) varied in different countries and ethnic groups from 7 to 35% in both sexes. There are several types of autoantibodies responsible for the immunoserological presentation of autoimmune thyroid diseases (AITDs) which can be either stimulating or inhibiting, which results in AITD being in the plus phase (thyrotoxicosis) or the minus phase (hypothyroidism). Different types of immune cells such as T cells, B cells, natural killer (NK) cells, antigen presenting cells (APCs), and other innate immune cells participate in the damage of the beta cells of the islets of Langerhans, which inevitably leads to T1D. Multiple genetic and environmental factors found in variable combinations are involved in the pathogenesis of AITD and T1D. In conclusion, although it is now well-known that both diabetes and thyroid diseases can affect fertility, only a few data are available on possible effects of autoimmune conditions. Recent findings nevertheless point to the importance of screening patients with immunologic infertility for AITDs and T1D, and vice versa
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Erectile dysfunction and its management in patients with diabetes mellitus
Full text linkDiabetes can be described as a syndrome of multiple closely related conditions induced by a chronic state of hyperglycaemia resulting from defective insulin secretion, insulin action or both. Chronic complications associated with diabetes (including neuropathy, vascular disease, nephropathy and retinopathy) are common, and of these, erectile dysfunction (ED) deserves special attention. ED and its correlation with cardiovascular disease require careful evaluation and appropriate treatment. PDE5 inhibitors (PDE5is) are an important tool for the treatment of ED, with new drugs coming onto the market since the late 90s. This review offers an overview of PDE5is and their use in treating ED in diabetes. We underline the differences between different types of PDE5i, focusing on available doses, duration of action, T 1⁄2, side effects and selectivity profiles in relation to patients with diabetes. We also discuss the link between diabetes and ED in presence of various associated cofactors (obesity, hypertension and its pharmacological treatments, atherosclerosis, hyperhomocysteinaemia, neuropathy, nephropathy, hypogonadism and depression). Finally a number of past and ongoing clinical trials on the use of PDE5is in patients with diabetes are presented to offer an overview of the appropriate treatment of ED in this condition
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