Potential Functions of the BMP Family in Bone, Obesity, and Glucose Metabolism

Characteristic bone metabolism was observed in obesity and diabetes with controversial conclusions. Type 2 diabetes (T2DM) and obesity may manifest increased bone mineral density. Also, obesity is more easily to occur in T2DM. Therefore, we infer that some factors may be linked to bone and obesity as well as glucose metabolism, which regulate all of them. Bone morphogenetic proteins (BMPs), belonging to the transforming growth factor- (TGF-) beta superfamily, regulate a diverse array of cellular functions during development and in the adult. More and more studies revealed that there exists a relationship between bone metabolism and obesity as well as glucose metabolism. BMP2, BMP4, BMP6, BMP7, and BMP9 have been shown to affect the pathophysiological process of obesity and glucose metabolism beyond bone metabolism. They may exert functions in adipogenesis and differentiation as well as insulin resistance. In the review, we summarize the literature on these BMPs and their association with metabolic diseases including obesity and diabetes.

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Immunometabolism of obesity and diabetes: microbiota link compartmentalized immunity in the gut to metabolic tissue inflammation

Clinical Science ◽

10.1042/cs20150431 ◽

2015 ◽

Vol 129 (12) ◽

pp. 1083-1096 ◽

Cited By ~ 42

Author(s):

Joseph B. McPhee ◽

Jonathan D. Schertzer

Keyword(s):

Metabolic Disease ◽

Type 2 Diabetes ◽

Immune Responses ◽

Metabolic Diseases ◽

The Body ◽

Tissue Inflammation ◽

Gut Barrier Function ◽

Inflammatory Status ◽

Obesity And Diabetes

The bacteria that inhabit us have emerged as factors linking immunity and metabolism. Changes in our microbiota can modify obesity and the immune underpinnings of metabolic diseases such as Type 2 diabetes. Obesity coincides with a low-level systemic inflammation, which also manifests within metabolic tissues such as adipose tissue and liver. This metabolic inflammation can promote insulin resistance and dysglycaemia. However, the obesity and metabolic disease-related immune responses that are compartmentalized in the intestinal environment do not necessarily parallel the inflammatory status of metabolic tissues that control blood glucose. In fact, a permissive immune environment in the gut can exacerbate metabolic tissue inflammation. Unravelling these discordant immune responses in different parts of the body and establishing a connection between nutrients, immunity and the microbiota in the gut is a complex challenge. Recent evidence positions the relationship between host gut barrier function, intestinal T cell responses and specific microbes at the crossroads of obesity and inflammation in metabolic disease. A key problem to be addressed is understanding how metabolite, immune or bacterial signals from the gut are relayed and transferred into systemic or metabolic tissue inflammation that can impair insulin action preceding Type 2 diabetes.

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Associations of Bone Mineral Density and Bone Metabolism Indices with Urine Albumin to Creatinine Ratio in Chinese Patients with Type 2 Diabetes

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-0762-0341 ◽

2018 ◽

Vol 6 (01) ◽

pp. 50-55 ◽

Cited By ~ 2

Author(s):

Xin Zhao ◽

Xiao-Mei Zhang ◽

Ning Yuan ◽

Xiao-Feng Yu ◽

Li-Nong Ji

Keyword(s):

Bone Mineral Density ◽

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Bone Metabolism ◽

Early Stage ◽

Chinese Patients ◽

Creatinine Ratio ◽

Mineral Density ◽

Urine Albumin

Abstract Objective To identify correlations of bone mineral density (BMD) and bone metabolism indices with the urine albumin to creatinine ratio (ACR) as an indicator of nephropathy in Chinese patients with type 2 diabetes (T2D). Methods In this retrospective analysis, 297 patients with T2D were divided into 3 groups according to the urine ACR. Patients’ data were analyzed to identify associations of general conditions, blood glucose level, lipid levels, and uric acid level with BMD and bone metabolism indices. Results BMD at every location tested (femoral neck, trochanter, inside hip, Ward’s triangle, total hip, and lumbar vertebrae) was negatively correlated with the urine ACR (all p<0.05). Osteocalcin, beta-C-terminal telopeptide (β-CTX), and procollagen type 1 N- peptide (P1NP) were positively correlated with urine ACR (all p<0.05). Finally, 25-hydroxyvitamin D [25(OH)D] was negatively correlated with urine ACR (p<0.05). Multiple regression analysis with adjustment for age, body mass index, disease duration, and other clinical measurements revealed no significant correlation between urine ACR and BMD measurements or β-CTX (p>0.05). However, significant correlations remained between urine ACR and osteocalcin, P1NP, and 25(OH)D (p<0.05). The same results were obtained for postmenopausal women specifically, with the exception of a significant correlation between the ACR and β-CTX (p<0.05). Conclusion In the early stage of diabetic nephropathy, BMD changes and bone transformation acceleration may occur, and the acceleration of bone transformation may occur before the change in BMD. Therefore, it is important to monitor bone metabolism indices in the early stage of diabetic nephropathy in T2D patients.

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MECHANISMS IN ENDOCRINOLOGY: FXR signalling: a novel target in metabolic diseases

Acta Endocrinologica ◽

10.1530/eje-20-1410 ◽

2021 ◽

Vol 184 (5) ◽

pp. R193-R205

Author(s):

David P Sonne

Keyword(s):

Type 2 Diabetes ◽

Bile Acid ◽

Gastrointestinal Tract ◽

Glucose Metabolism ◽

Metabolic Diseases ◽

Farnesoid X Receptor ◽

Optimal Size ◽

Lipid Digestion ◽

Alcoholic Fatty Liver

During the last decades, it has become clear that the gastrointestinal tract plays a pivotal role in the regulation of glucose homeostasis. More than 40 hormones originate from the gastrointestinal tract and several of these impact glucose metabolism and appetite regulation. An astonishing example of the gut’s integrative role in glucose metabolism originates from investigations into bile acid biology. From primary animal studies, it has become clear that bile acids should no longer be labelled as simple detergents necessary for lipid digestion and absorption but should also be recognised as metabolic regulators implicated in lipid, glucose and energy metabolism. The nuclear farnesoid X receptor (FXR) is a part of an exquisite bile acid-sensing system that among other things ensures the optimal size of the bile acid pool. In addition, intestinal and hepatic FXR also impact the regulation of several metabolic processes such as glucose and lipid metabolism. Accordingly, natural and synthetic FXR agonists and certain FXR-regulated factors (i.e. fibroblast growth factor 19 (FGF19)) are increasingly being evaluated as treatments for metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease (and its inflammatory version, non-alcoholic steatohepatitis). Interestingly, decreased FXR activation also benefits glucose metabolism. This can be obtained by reducing bile acid absorption using bile acid sequestering agents (approved for the treatment of type 2 diabetes) or inhibitors of intestinal bile acid transporters,that is the apical sodium-dependent bile acid transporter (ASBT). This article discusses recent clinical trials that provide insights about the role of FXR-FGF19-targetted therapy for the treatment of metabolic diseases.

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Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Nature Communications ◽

10.1038/s41467-020-19589-w ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Antonio Molinaro ◽

◽

Pierre Bel Lassen ◽

Marcus Henricsson ◽

Hao Wu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glucose Metabolism ◽

Microbial Ecology ◽

Metabolic Diseases ◽

Elevated Serum ◽

Bacterial Gene ◽

Host Diet ◽

Per Se ◽

Gene Richness

AbstractMicrobiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.

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The Beige Adipocyte as a Therapy for Metabolic Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms20205058 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5058 ◽

Cited By ~ 16

Author(s):

Fernando Lizcano

Keyword(s):

Diabetes Mellitus ◽

Adipose Tissue ◽

Diabetes Mellitus Type 2 ◽

Metabolic Diseases ◽

Brown Fat ◽

Diabetes Mellitus Type ◽

Beige Adipocyte ◽

Obesity And Diabetes ◽

Beige Adipocytes

Adipose tissue is traditionally categorized into white and brown relating to their function and morphology. The classical white adipose tissue builds up energy in the form of triglycerides and is useful for preventing fatigue during periods of low caloric intake and the brown adipose tissue more energetically active, with a greater number of mitochondria and energy production in the form of heat. Since adult humans possess significant amounts of active brown fat depots and its mass inversely correlates with adiposity, brown fat might play an important role in human obesity and energy homeostasis. New evidence suggests two types of thermogenic adipocytes with distinct developmental and anatomical features: classical brown adipocytes and beige adipocytes. Beige adipocyte has recently attracted special interest because of its ability to dissipate energy and the possible ability to differentiate themselves from white adipocytes. The presence of brown and beige adipocyte in human adults has acquired attention as a possible therapeutic intervention for metabolic diseases. Importantly, adult human brown appears to be mainly composed of beige-like adipocytes, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, such as atherosclerosis, arterial hypertension and diabetes mellitus type 2. Because many epigenetics changes can affect beige adipocyte differentiation from adipose progenitor cells, the knowledge of the circumstances that affect the development of beige adipocyte cells may be important to new pathways in the treatment of metabolic diseases. New molecules have emerged as possible therapeutic targets, which through the impulse to develop beige adipocytes can be useful for clinical studies. In this review will discuss some recent observations arising from the unique physiological capacity of these cells and their possible role as ways to treat obesity and diabetes mellitus type 2.

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Bone Morphogenetic Proteins and Their Receptors in the Eye

Experimental Biology and Medicine ◽

10.3181/0510-mr-345 ◽

2007 ◽

Vol 232 (8) ◽

pp. 979-992 ◽

Cited By ~ 53

Author(s):

Robert J. Wordinger ◽

Abbot F. Clark

Keyword(s):

Growth Factor ◽

Bone Morphogenetic Proteins ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Bmp Signaling ◽

Receptor Expression ◽

Future Research ◽

Cellular Functions ◽

Ocular Tissues ◽

Bmp Receptors

The human genome encodes at least 42 different members of the transforming growth factor-β superfamily of growth factors. Bone morphogenetic proteins (BMPs) are the largest subfamily of proteins within the transforming growth factor-β superfamily and are involved in numerous cellular functions including development, morphogenesis, cell proliferation, apoptosis, and extracellular matrix synthesis. This article first reviews BMPs and BMP receptors, BMP signaling pathways, and mechanisms controlling BMP signaling. Second, we review BMP and BMP receptor expression during embryonic ocular development/ differentiation and in adult ocular tissues. Lastly, future research directions with respect to BMP, BMP receptors, and ocular tissues are suggested.

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Chemerin Exacerbates Glucose Intolerance in Mouse Models of Obesity and Diabetes

Endocrinology ◽

10.1210/en.2009-1098 ◽

2010 ◽

Vol 151 (5) ◽

pp. 1998-2007 ◽

Cited By ~ 143

Author(s):

Matthew C. Ernst ◽

Mark Issa ◽

Kerry B. Goralski ◽

Christopher J. Sinal

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Glucose Metabolism ◽

Mouse Models ◽

Glucose Intolerance ◽

Serum Insulin ◽

Serum Levels ◽

Established Risk Factor ◽

Obesity And Diabetes

Obesity, characterized by an excess of adipose tissue, is an established risk factor for cardiovascular disease and type 2 diabetes. Different mechanisms linking obesity with these comorbidities have been postulated but remain poorly understood. Adipose tissue secretes a number of hormone-like compounds, termed adipokines, that are important for the maintenance of normal glucose metabolism. Alterations in the secretion of adipokines with obesity are believed to contribute to the undesirable changes in glucose metabolism that ultimately result in the development of type 2 diabetes. In the present study, we have shown that serum levels of the novel adipokine chemerin are significantly elevated in mouse models of obesity/diabetes. The expression of chemerin and its receptors, chemokine-like receptor 1, chemokine (C-C motif) receptor-like 2, and G protein-coupled receptor 1 are altered in white adipose, skeletal muscle, and liver tissue of obese/diabetic mice. Administration of exogenous chemerin exacerbates glucose intolerance, lowers serum insulin levels, and decreases tissue glucose uptake in obese/diabetic but not normoglycemic mice. Collectively, these data indicate that chemerin influences glucose homeostasis and may contribute to the metabolic derangements characteristic of obesity and type 2 diabetes.

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Osteocalcin: the relationship between bone metabolism and glucose homeostasis in diabetes mellitus

INTERNATIONAL JOURNAL OF ENDOCRINOLOGY ◽

10.22141/2224-0721.17.4.2021.237347 ◽

2021 ◽

Vol 17 (4) ◽

pp. 322-328

Author(s):

A.V. Кovalchuk ◽

О.В. Zinych ◽

V.V. Korpachev ◽

N.M. Кushnareva ◽

О.В. Prybyla ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Bone Metabolism ◽

The Body ◽

Diabetic Patients ◽

Inverse Association ◽

Mineral Density ◽

Peripheral Tissues

Recent studies have demonstrated the importance of bone as an endocrine organ that produces biologically active substances, which regulate both local bone metabolism and metabolic functions throughout the body. In the process of bone remodeling (formation/destruction), the active cells secrete specific biomarkers that help detect osteometabolic dysfunction. Among bone hormones, osteocalcin plays an important role as a coordinator of bone modeling processes, energy homeostasis, metabolism of glucose, lipids and minerals. Osteocalcin is a structural protein of the bone matrix, which is synthesized by osteoblasts and enters the bloodstream in the process of bone resorption. The level of osteocalcin in the serum is used as a specific marker of bone formation. Osteocalcin promotes pancreatic β-cell proliferation and insulin secretion, and also affects the insulin sensitivity of peripheral tissues. The inverse association of glycemia with the level of osteocalcin was revealed. Patients with type 2 diabetes mellitus usually have normal or even slightly elevated bone mineral density compared to age-appropriate controls. Decreased bone quality and increased risk of fractures are associated with changes in bone microarchitecture and local humoral environment. An imbalance in osteoblast/osteoclast activity may be due to oxidative stress and the accumulation of glycosylation end products, which contributes to chronic inflammation and bone resorbtion in patients with diabetes. It is shown that the level of osteocalcin in the blood serum is significantly reduced compared to healthy controls, both in patients with type 1 diabetes mellitus and, especially, in type 2 diabetes mellitus. Given the importance of developing new approaches to the diagnosis and correction of metabolic disorders in diabetic patients, the study of the influence of bone hormones on hormonal and metabolic parameters and bone status, including the risk of fractures, remains relevant in modern diabetology.

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Advantages of Phosphodiesterase Type 5 Inhibitors in the Management of Glucose Metabolism Disorders: A Clinical and Translational Issue

International Journal of Endocrinology ◽

10.1155/2020/7078108 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Cristina Antinozzi ◽

Paolo Sgrò ◽

Luigi Di Luigi

Keyword(s):

Type 2 Diabetes ◽

Glucose Metabolism ◽

Metabolic Diseases ◽

Heart Diseases ◽

Protective Action ◽

Clinical Aspects ◽

Glucose Metabolism Disorders ◽

Phosphodiesterase Type 5 Inhibitors ◽

Phosphodiesterase Type

Among metabolic diseases, carbohydrate metabolism disorders are the most widespread. The most common glucose pathological conditions are acquired and may increase the risk of type 2 diabetes, obesity, heart diseases, stroke, and kidney insufficiency. Phosphodiesterase type 5 inhibitors (PDE5i) have long been used as an effective therapeutic option for the treatment of erectile dysfunction (ED). Different studies have demonstrated that PDE5i, by sensitizing insulin target tissues to insulin, play an important role in controlling the action of insulin and glucose metabolism, highlighting the protective action of these drugs against metabolic diseases. In this review, we report the latest knowledge about the role of PDE5i in the metabolic diseases of insulin resistance and type 2 diabetes, highlighting clinical aspects and potential treatment approaches. Although various encouraging data are available, further in vivo and in vitro studies are required to elucidate the mechanism of action and their clinical application in humans.

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Astrocyte Clocks and Glucose Homeostasis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.662017 ◽

2021 ◽

Vol 12 ◽

Author(s):

Olga Barca-Mayo ◽

Miguel López

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Circadian Clock ◽

Glucose Homeostasis ◽

Metabolic Diseases ◽

Current Knowledge ◽

Genetic Alterations ◽

Whole Body

The endogenous timekeeping system evolved to anticipate the time of the day through the 24 hours cycle of the Earth’s rotation. In mammals, the circadian clock governs rhythmic physiological and behavioral processes, including the daily oscillation in glucose metabolism, food intake, energy expenditure, and whole-body insulin sensitivity. The results from a series of studies have demonstrated that environmental or genetic alterations of the circadian cycle in humans and rodents are strongly associated with metabolic diseases such as obesity and type 2 diabetes. Emerging evidence suggests that astrocyte clocks have a crucial role in regulating molecular, physiological, and behavioral circadian rhythms such as glucose metabolism and insulin sensitivity. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying glucose homeostasis regulation by the circadian clock and its dysregulation may improve glycemic control. In this review, we summarize the current knowledge on the tight interconnection between the timekeeping system, glucose homeostasis, and insulin sensitivity. We focus specifically on the involvement of astrocyte clocks, at the organism, cellular, and molecular levels, in the regulation of glucose metabolism.

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