Roles of bone-derived hormones in type 2 diabetes and cardiovascular pathophysiology

Background: Emerging evidence demonstrates that bone is an endocrine organ capable of influencing multiple physiological and pathological processes through the secretion of hormones. Recent research suggests complex crosstalk between the bone and other metabolic and cardiovascular tissues. It was uncovered that three of these bone-derived hormones—osteocalcin, lipocalin 2, and sclerostin—are involved in the endocrine regulations of cardiometabolic health and play vital roles in the pathophysiological process of developing cardiometabolic syndromes such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation is one of the hallmarks of cardiometabolic diseases and a major contributor to disease progression. Novel evidence also implicates important roles of bone-derived hormones in the regulation of chronic inflammation. Scope of review: In this review, we provide a detailed overview of the physiological and pathological roles of osteocalcin, lipocalin 2, and sclerostin in cardiometabolic health regulation and disease development, with a focus on the modulation of chronic inflammation. Major conclusions: Evidence supports that osteocalcin has a protective role in cardiometabolic health, and an increase of lipocalin 2 contributes to the development of cardiometabolic diseases partly via pro-inflammatory effects. The roles of sclerostin appear to be complicated: It exerts pro-adiposity and pro-insulin resistance effects in type 2 diabetes and has an anti-calcification effect during cardiovascular disease. A better understanding of the actions of these bone-derived hormones in the pathophysiology of cardiometabolic diseases will provide crucial insights to help further research develop new therapeutic strategies to treat these diseases

Undercarboxylated Osteocalcin: Experimental and Human Evidence for a Role in Glucose Homeostasis and Muscle Regulation of Insulin Sensitivity

Recent advances have indicated that osteocalcin, and in particular its undercarboxylated form (ucOC), is not only a nutritional biomarker reflective of vitamin K status and an indicator of bone health but also an active hormone that mediates glucose metabolism in experimental studies. This work has been supported by the putative identification of G protein-coupled receptor, class C, group 6, member A (GPRC6A) as a cell surface receptor for ucOC. Of note, ucOC has been associated with diabetes and with cardiovascular risk in epidemiological studies, consistent with a pathophysiological role for ucOC in vivo. Limitations of existing knowledge include uncertainty regarding the underlying mechanisms by which ucOC interacts with GPRC6A to modulate metabolic and cardiovascular outcomes, technical issues with commonly used assays for ucOC in serum, and a paucity of clinical trials to prove causation and illuminate the scope for novel health interventions. A key emerging area of research is the role of ucOC in relation to expression of GPRC6A in muscle, and whether exercise interventions may modulate metabolic outcomes favorably in part via ucOC. Further research is warranted to clarify potential direct and indirect roles for ucOC in human health and cardiometabolic diseases

The effects of acute exercise on bone turnover markers in middle-aged and older adults: A systematic review

© 2020 Elsevier Inc. Background: Bone turnover is the cellular machinery responsible for bone integrity and strength and, in the clinical setting, it is assessed using bone turnover markers (BTMs). Acute exercise can induce mechanical stress on bone which is needed for bone remodelling, but to date, there are conflicting results in regards to the effects of varying mechanical stimuli on BTMs. Objectives: This systematic review examines the effects of acute aerobic, resistance and impact exercises on BTMs in middle and older-aged adults and examines whether the responses are determined by the exercise mode, intensity, age and sex. Methods: We searched PubMed, SCOPUS, Web of Science and EMBASE up to 22nd April 2020. Eligibility criteria included randomised controlled trials (RCTs) and single-arm studies that included middle-aged (50 to 65 years) and older adults (\u3e65 years) and, a single-bout, acute-exercise (aerobic, resistance, impact) intervention with measurement of BTMs. PROSPERO registration number CRD42020145359. Results: Thirteen studies were included; 8 in middle-aged (n = 275, 212 women/63 men, mean age = 57.9 ± 1.5 years) and 5 in older adults (n = 93, 50 women/43 men, mean age = 68.2 ± 2.2 years). Eleven studies included aerobic exercise (AE, 7 middle-aged/4 older adults), and two included resistance exercise (RE, both middle-aged). AE significantly increased C-terminal telopeptide (CTX), alkaline phosphatase (ALP) and bone-ALP in middle-aged and older adults. AE also significantly increased total osteocalcin (tOC) in middle-aged men and Procollagen I Carboxyterminal Propeptide and Cross-Linked Carboxyterminal Telopeptide of Type I Collagen in older women. RE alone decreased ALP in older adults. In middle-aged adults, RE with impact had no effect on tOC or BALP, but significantly decreased CTX. Impact (jumping) exercise alone increased Procollagen Type 1 N Propeptide and tOC in middle-aged women. Conclusion: Acute exercise is an effective tool to modify BTMs, however, the response appears to be exercise modality-, intensity-, age- and sex-specific. There is further need for higher quality and larger RCTs in this area

The Effects of Acute High-Intensity Interval Exercise and Hyperinsulinemic-Euglycemic Clamp on Osteoglycin Levels in Young and Middle-Aged Men

Osteoglycin (OGN) is a leucine-rich proteoglycan that has been implicated in the regulation of glucose in animal models. However, its relationship with glucose control in humans is unclear. We examined the effect of high-intensity interval exercise (HIIE) and hyperinsulinemic-euglycemic clamp on circulating levels of OGN as well as whether circulating OGN levels are associated with markers of glycemic control and cardio-metabolic health. Serum was analyzed for OGN (ELISA) levels from 9 middle-aged obese men (58.1 ± 2.2 years, body mass index [BMI] = 33.1 ± 1.4 kg∙m−2, mean ± SEM) and 9 young men (27.8 ± 1.6 years, BMI = 24.4 ± 0.08 kg∙m−2) who previously completed a study involving a euglycemic-hyperinsulinemic clamp at rest and after HIIE (4x4 minutes cycling at approximately 95% peak heart rate (HRpeak), interspersed with 2 minutes of active recovery). Blood pressure, body composition (dual-energy X-ray absorptiometry), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) were assessed. Serum OGN was higher in the young cohort compared with the middle-aged cohort (65.2 ± 10.1 ng/mL versus 36.5 ± 4. 5 ng/mL, p ≤ 0.05). Serum OGN was unaffected by acute HIIE but decreased after the insulin clamp compared with baseline (~−27%, p = 0.01), post-exercise (~−35%, p = 0.01), and pre-clamp (~−32%, p = 0.02) time points, irrespective of age. At baseline, lower circulating OGN levels were associated with increased age, BMI, and fat mass, whereas higher OGN levels were related to lower fasting glucose. Higher OGN levels were associated with a higher glucose infusion rate. Exercise had a limited effect on circulating OGN. The mechanisms by which OGN affects glucose regulation should be explored in the future. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research

The effects of acute high-intensity interval exercise and hyperinsulinemic-euglycemic clamp on osteoglycin levels in young and middle-aged men

Osteoglycin (OGN) is a leucine-rich proteoglycan that has been implicated in the regulation of glucose in animal models. However, its relationship with glucose control in humans is unclear. We examined the effect of high-intensity interval exercise (HIIE) and hyperinsulinemic-euglycemic clamp on circulating levels of OGN as well as whether circulating OGN levels are associated with markers of glycemic control and cardio-metabolic health. Serum was analyzed for OGN (ELISA) levels from 9 middle-aged obese men (58.1 ± 2.2 years, body mass index [BMI] = 33.1 ± 1.4 kg∙m − 2, mean ± SEM) and 9 young men (27.8 ± 1.6 years, BMI = 24.4 ± 0.08 kg∙m − 2) who previously completed a study involving a euglycemic-hyperinsulinemic clamp at rest and after HIIE (4 x 4 minutes cycling at approximately 95% peak heart rate (HRpeak), interspersed with 2 minutes of active recovery). Blood pressure, body composition (dual-energy X-ray absorptiometry), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) were assessed. Serum OGN was higher in the young cohort compared with the middle-aged cohort (65.2 ± 10.1 ng/mL versus 36.5 ± 4. 5 ng/mL, p ≤ 0.05). Serum OGN was unaffected by acute HIIE but decreased after the insulin clamp compared with baseline (~ − 27 %, p = 0.01), post-exercise (~ − 35 %, p = 0.01), and pre-clamp (~ − 32 %, p = 0.02) time points, irrespective of age. At baseline, lower circulating OGN levels were associated with increased age, BMI, and fat mass, whereas higher OGN levels were related to lower fasting glucose. Higher OGN levels were associated with a higher glucose infusion rate. Exercise had a limited effect on circulating OGN. The mechanisms by which OGN affects glucose regulation should be explored in the future

Recombinant Uncarboxylated Osteocalcin Per Se Enhances Mouse Skeletal Muscle Glucose Uptake in both Extensor Digitorum Longus and Soleus Muscles

Emerging evidence suggests that undercarboxylated osteocalcin (ucOC) improves muscle glucose uptake in rodents. However, whether ucOC can directly increase glucose uptake in both glycolytic and oxidative muscles and the possible mechanisms of action still need further exploration. We tested the hypothesis that ucOC per se stimulates muscle glucose uptake via extracellular signal-regulated kinase (ERK), adenosine monophosphate-activated protein kinase (AMPK), and/or the mechanistic target of rapamycin complex 2 (mTORC2)-protein kinase B (AKT)-AKT substrate of 160 kDa (AS160) signaling cascade. Extensor digitorum longus (EDL) and soleus muscles from male C57BL/6 mice were isolated, divided into halves, and then incubated with ucOC with or without the pretreatment of ERK inhibitor U0126. ucOC increased muscle glucose uptake in both EDL and soleus. It also enhanced phosphorylation of ERK2 (Thr202/Tyr204) and AS160 (Thr642) in both muscle types and increased mTOR phosphorylation (Ser2481) in EDL only. ucOC had no significant effect on the phosphorylation of AMPKa (Thr172). The inhibition of ucOC-induced ERK phosphorylation had limited effect on ucOC-stimulated glucose uptake and AS160 phosphorylation in both muscle types, but appeared to inhibit the elevation in AKT phosphorylation only in EDL. Taken together, ucOC at the physiological range directly increased glucose uptake in both EDL and soleus muscles in mouse. The molecular mechanisms behind this ucOC effect on muscle glucose uptake seem to be muscle type-specific, involving enhanced phosphorylation of AS160 but limitedly modulated by ERK phosphorylation. Our study suggests that, since ucOC increases muscle glucose uptake without insulin, it could be considered as a potential agent to improve muscle glucose uptake in insulin resistant conditions

Normal increases in insulin-stimulated glucose uptake after ex vivo contraction in neuronal nitric oxide synthase mu (nNOSμ) knockout mice

Nitric oxide (NO) is involved in skeletal muscle glucose uptake during exercise and also in the increase in insulin sensitivity after exercise. Given that neuronal nitric oxide synthase (NOS) isoform mu (nNOSμ) is a major isoform of NOS in skeletal muscle, we examined if the increase in skeletal muscle insulin-stimulated glucose uptake 3.5 h following ex vivo contraction of extensor digitorum longus (EDL) is reduced in muscles from nNOSμ +/− and nNOSμ −/− mice compared with nNOSμ +/+ mice. 3.5 h post-contraction/basal, muscles were exposed to saline or insulin (120μU/ml) with or without the presence of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) during the last 30 min and glucose uptake was determined by radioactive tracers. Skeletal muscle insulin-stimulated glucose uptake from nNOSμ +/+ , nNOSμ +/− , and nNOSμ −/− mice increased approximately twofold 3.5 h following ex vivo contraction when compared to rest. L-NMMA significantly attenuated this increase in muscle insulin-stimulated glucose uptake by around 50%, irrespective of genotype. Low levels of NOS activity were detected in muscles from nNOSμ −/− mice. In conclusion, NO mediates increases in mouse skeletal muscle insulin response following ex vivo contraction independently of nNOSμ

Liquid Biopsy, ctDNA Diagnosis through NGS

Liquid biopsy with circulating tumor DNA (ctDNA) profiling by next-generation sequencing holds great promise to revolutionize clinical oncology. It relies on the basis that ctDNA represents the real-time status of the tumor genome which contains information of genetic alterations. Compared to tissue biopsy, liquid biopsy possesses great advantages such as a less demanding procedure, minimal invasion, ease of frequent sampling, and less sampling bias. Next-generation sequencing (NGS) methods have come to a point that both the cost and performance are suitable for clinical diagnosis. Thus, profiling ctDNA by NGS technologies is becoming more and more popular since it can be applied in the whole process of cancer diagnosis and management. Further developments of liquid biopsy ctDNA testing will be beneficial for cancer patients, paving the way for precision medicine. In conclusion, profiling ctDNA with NGS for cancer diagnosis is both biologically sound and technically convenient