Interaction between bone and glucose metabolism [Review]

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Abstract

Accumulating evidence has shown that bone and glucose metabolism are closely associated with each other. Since the risk of osteoporotic fractures is increased in patients with diabetes mellitus (DM), osteoporosis is recently recognized as one of diabetic complications, called DM-induced bone fragility. Previous studies showed that collagen cross-links of advanced glycation end products (AGEs) and dysfunctions of osteoblast and osteocyte are involved in DM-induced bone fragility. Circulating levels of AGEs and homocysteine are increased in patients with DM, and they directly impair the functions of osteoblast and osteocyte, resulting in decreased bone formation and bone remodeling. On the other hand, bone is recently recognized as an endocrine organ. Previous studies based on in vitro and animal studies showed that osteocalcin, which is specifically expressed in osteoblasts and secreted into the circulation, may regulate glucose homeostasis. Although several clinical studies reported the relationship between osteocalcin and glucose metabolism, further large-scale and intervention studies are necessary to confirm the beneficial effects of osteocalcin on glucose metabolism in human. It has been shown that adenosine monophosphate-activated protein kinase (AMPK), an intracellular energy sensor, is involved in bone metabolism. Adiponectin and metformin stimulate osteocalcin expression and the differentiation of osteoblasts via AMPK activation. Also, AMPK activation protects against oxidative stress-induced apoptosis of osteocytes. These findings suggest that AMPK in osteoblasts and osteocytes may be a therapeutic target for DM-induced bone fragility.

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Most cited references 48

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Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture.

Mohsen Janghorbani, Rob Van Dam, Walter C. Willett … (2007)

The authors conducted a systematic review of published data on the association between diabetes mellitus and fracture. The authors searched MEDLINE through June 2006 and examined the reference lists of pertinent articles (limited to studies in humans). Summary relative risks and 95% confidence intervals were calculated with a random-effects model. The 16 eligible studies (two case-control studies and 14 cohort studies) included 836,941 participants and 139,531 incident cases of fracture. Type 2 diabetes was associated with an increased risk of hip fracture in both men (summary relative risk (RR) = 2.8, 95% confidence interval (CI): 1.2, 6.6) and women (summary RR = 2.1, 95% CI: 1.6, 2.7). Results were consistent between studies of men and women and between studies conducted in the United States and Europe. The association between type of diabetes and hip fracture incidence was stronger for type 1 diabetes (summary RR = 6.3, 95% CI: 2.6, 15.1) than for type 2 diabetes (summary RR = 1.7, 95% CI: 1.3, 2.2). Type 2 diabetes was weakly associated with fractures at other sites, and most effect estimates were not statistically significant. These findings strongly support an association between both type 1 and type 2 diabetes and increased risk of hip fracture in men and women.

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AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan

Antero Salminen, Juha M. T. Hyttinen, Kai Kaarniranta (2011)

Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of energy metabolic homeostasis and thus a major survival factor in a variety of metabolic stresses and also in the aging process. Metabolic syndrome is associated with a low-grade, chronic inflammation, primarily in adipose tissue. A low-level of inflammation is also present in the aging process. There are emerging results indicating that AMPK signaling can inhibit the inflammatory responses induced by the nuclear factor-κB (NF-κB) system. The NF-κB subunits are not direct phosphorylation targets of AMPK, but the inhibition of NF-κB signaling is mediated by several downstream targets of AMPK, e.g., SIRT1, PGC-1α, p53, and Forkhead box O (FoxO) factors. AMPK signaling seems to enhance energy metabolism while it can repress inflammatory responses linked to chronic stress, e.g., in nutritional overload and during the aging process. AMPK can inhibit endoplasmic reticulum and oxidative stresses which are involved in metabolic disorders and the aging process. Interestingly, many target proteins of AMPK are so-called longevity factors, e.g., SIRT1, p53, and FoxOs, which not only can increase the stress resistance and extend the lifespan of many organisms but also inhibit the inflammatory responses. The activation capacity of AMPK declines in metabolic stress and with aging which could augment the metabolic diseases and accelerate the aging process. We will review the AMPK pathways involved in the inhibition of NF-κB signaling and suppression of inflammation. We also emphasize that the capacity of AMPK to repress inflammatory responses can have a significant impact on both healthspan and lifespan.

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Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk.

L Rejnmark, P Vestergaard, L Mosekilde (2005)

We studied the association between fractures and type 1 and type 2 diabetes mellitus. In this case-control study, all subjects diagnosed with a fracture (n=124,655) in Denmark served as cases, and for each case three control subjects (n=373,962) matched for sex and age were retrieved from the general population. Type 1 and type 2 diabetes were associated with an increased risk (1) of any fracture (odds ratio [OR]=1.3, 95% CI: 1.2-1.5 for type 1 diabetes and 1.2, 95% CI: 1.1-1.3 for type 2 diabetes after adjustment for confounders) and (2) of hip fractures (OR=1.7, 95% CI: 1.3-2.2 for type 1 diabetes, and 1.4, 95% CI: 1.2-1.6 for type 2 diabetes). Furthermore, type 2 diabetes was associated with a significant increase in forearm fractures (OR=1.2, 95% CI: 1.0-1.5), and type 1 diabetes was associated with an increased risk of spine fractures (OR=2.5, 95% CI: 1.3-4.6), whereas type 2 diabetes was not. Use of metformin and sulphonylureas was associated with a significantly decreased risk of any fracture, whereas a non-significant trend towards decreased risk of any fracture was associated with the use of insulin. Except for a decrease in hip fractures with use of sulphonylureas, no change in fracture risk in the hip, spine or forearm was associated with the use of insulin or oral antidiabetic drugs. Type 1 and type 2 diabetes are associated with an increased risk of any fracture and hip fractures. The use of drugs to control diabetes may reduce the association between diabetes and fractures.

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Author and article information

Journal

Title: Endocrine Journal

Abbreviated Title: Endocr J

Publisher: Japan Endocrine Society

ISSN (Print): 0918-8959

ISSN (Electronic): 1348-4540

Publication date Created: 2017

Publication date (Print): 2017

Volume: 64

Issue: 11

Pages: 1043-1053

Affiliations

[1 ]Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan

Article

DOI: 10.1507/endocrj.EJ17-0323

PubMed ID: 28966224

SO-VID: d816aa0b-1f59-4bdd-80ab-9b3cb0264584

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