Bone-Derived Factors in the Treatment of Diabetes

The increasing prevalence of type 2 diabetes (T2D) and prediabetes underscores the need for novel approaches to diabetes diagnosis, prevention, and treatment. In addition to organs with a well-established role in diabetes pathogenesis, a growing body of research highlights the important role of bone in glucose metabolism.¹ In contrast to other affected organs, aerobic glycolysis is the primary pathway for glucose utilization in the skeleton.

The emerging evidence points to the “possibility that we can treat, prevent, and predict diabetes in humans by using ‘osteokines’ which are molecules derived from the bone that modulate various pathophysiological functions in other tissues,” wrote the authors of a 2018 review published in Diabetes, Obesity & Metabolism.¹ Selected findings described in their paper are summarized below:

• The osteoblast-derived protein osteocalcin is a marker of bone turnover that, in its active form undercarboxylated osteocalcin, has been found to promote insulin expression, secretion, and sensitivity, as well as glucose and fatty acid uptake in rodents. Osteocalcin was “redefined as an endocrine hormone when [osteocalcin]-deleted mice showed [hypoinsulinemia], [hyperglycemia], glucose intolerance, and insulin resistance,” according to the review.1

  Various findings have demonstrated that undercarboxylated osteocalcin increases serum insulin levels by promoting pancreatic β-cell proliferation and insulin expression and secretion. It has also been shown that undercarboxylated osteocalcin improves insulin resistance by means of upregulation of adiponectin, an adipokine that facilitates insulin sensitivity. Osteocalcin also stimulates insulin secretion indirectly by promoting the release of glucagon-like peptide-1 in intestinal epithelial cells.¹

  Similar observations were found in cultured human islets, with undercarboxylated osteocalcin-mediated β-cell proliferation and differentiation and increased insulin production.² Several cross-sectional studies of patients with T2D have reported negative associations between higher serum levels of osteocalcin and fasting plasma glucose and hemoglobin (Hb) A1c levels,^3-6 and large studies conducted in China and Japan indicated a higher risk for prediabetes and T2D among individuals with lower baseline serum levels of osteocalcin.¹

• The osteoblast-derived lipocalin 2 (LCN2) has been found to regulate appetite through hypothalamic action.⁷ Various rodent and human studies have demonstrated the influence of LCN2 on feeding regulation, including a 2017 study that noted increased circulating levels of postprandial LCN2 in mice and an associated reduction in food intake.⁷ This increase in LCN2 “seems to contribute to postprandial satiety, as restoration of LCN2 levels in Lcn2 null mice corrected the rebound hyperphagia induced by fasting,” wrote the authors of the 2018 review.1

  In a clinical study published in 2013, normal-weight participants exhibited significant increases in postprandial serum LCN2 levels after consuming a high-fat meal, whereas levels decreased among individuals with obesity.⁸ The reasons for this discrepancy are unclear. “Whether LCN2 resistance occurs in obesity, whether LCN2 is induced by underlying inflammation to combat the deleterious effects of obesity, or whether there is even a change in the function of LCN2 under various pathophysiological conditions remain open questions and require further research.”¹

  In recent rodent studies, Lcn2-deficient mice exhibited hyperphagia, increased fat mass and body weight, fasted hypoglycemia, hyperinsulinemia, glycorsuria, and polyuria vs wild-type mice.¹ When rodents in another investigation were administered exogenous LCN2, they experienced reduced food intake, body weight, and fat mass, along with improved glucose tolerance, insulin secretion, and energy expensiture.⁷

• Osteocyte-secreted molecules such as bone morphogenetic protein 7 (BMP7) and sclerostin may also have a potential role in diabetes management.

  BMP7 has long been reported to reduce food intake and stimulate brown adipogenesis, thus improving energy metabolism.¹ In a 2011 study of adults without diabetes, BMP7 was positively linked with the insulin secretion index and fasting insulin, indicating that the protein may prompt insulin secretion and fasting insulin.⁹ Bone, heart, kidney, and other tissues express BMP7; however, the primary sources of circulating BMP7 are unknown.

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  Sclerostin has been shown to have positive associations with body mass index, fat mass, and insulin resistance. Some studies have recorded elevated sclerostin levels in patients with impaired glucose regulation, type 1 diabetes, and T2D, although findings from other research on the topic have varied.¹

Additional bone-derived factors implicated in glucose homeostasis that warrant further investigation include receptor activator of nuclear factor κ-B ligand (RANKL) and neuropeptide Y.¹ Valuable insights may also result from following long-term glucose-related outcomes in individuals taking an anti-RANKL or anti-sclerostin monoclonal antibody for osteoporosis.

Endocrinology Advisor checked in with review co-author Jian-min Liu, PhD, of the Shanghai Clinical Center for Endocrine and Metabolic Diseases, to learn more about the link between bone and glucose metabolism.

Endocrinology Advisor: Overall, what is known about the relationship between bone and glucose metabolism?

Dr Liu: Mice studies have clearly demonstrated that osteocalcin, which is synthesized and released from bone, especially in its metabolic active form (undercarboxylated osteocalcin), can stimulate insulin secretion and improve insulin resistance. In addition, LCN2, another bone-derived factor, could inhibit appetite and reduce body weight.

It is also well recognized that in humans, serum osteocalcin levels have a positive relationship with fasting plasma glucose and HbA1c levels in patients with [type 1 diabetes], T2D, metabolic syndrome, [polycystic ovary syndrome], [gestational diabetes], and so on.

Endocrinology Advisor: What are the potential implications of such findings for diabetes prevention and treatment?

Dr Liu: Although lifestyle modifications including exercise and diet control are the main approaches to prevent diabetes, these endeavors are not easy for patients. Rodent studies have shown that osteocalcin improved muscle power and enhanced exercise capacity, while LPN2 acts as an appetite suppressor. Human studies have shown that with increasing age, both of these osteokines decrease. If we can improve the ability to exercise and reduce food intake with osteocalcin and LPN2, these would be helpful in preventing diabetes. However, there is much work to be done on these topics.

For diabetes treatment, the current medications focus on the 8 core pathophysiologic defects that comprise the “ominous octet.” However, bone is a missing piece in this area. Osteocalcin shows promise for diabetes treatment because of  its direct actions on pancreatic beta cells and the small intestine to stimulate insulin and [glucagon-like peptide-1] secretion, respectively.

Endocrinology Advisor: What should be the focus of future research on this topic?

Dr Liu: Although results are encouraging thus far, we are unclear on whether the results observed in mice could be extrapolated to humans. We need to prove, for example, that LPN2 could pass through the blood-brain barrier to exert its central anorexic effect in humans as it does in mice, and the antidiabetic efficacy of osteocalcin should be tested and confirmed in humans in clinical trials. Other bone-derived factors that could affect glucose metabolism should be also be explored, and the potential impact of anti-osteoporotic medications on glucose metabolism should be evaluated.

Edited and revised for clarity by Endocrinology Advisor.

References

1. Liu DM, Mosialou I, Liu JM. Bone: another potential target to treat, prevent and predict diabetes. Diabetes Obes Metab. 2018;20(8):1817-1828.

2. Sabek OM, Nishimoto SK, Fraga D, Tejpal N, Ricordi C, Gaber AO. Osteocalcin effect on human beta-cells mass and function.  Endocrinology. 2015;156(9):3137-3146.

3. Bae SJ, Choe JW, Chung YE, et al. The association between serum osteocalcin levels and metabolic syndrome in Koreans.  Osteoporos Int. 2011;22(11):2837-2846.

4. Bao Y, Zhou M, Lu Z, et al. Serum levels of osteocalcin are inversely associated with the metabolic syndrome and the severity of coronary artery disease in Chinese men.  Clin Endocrinol (Oxf). 2011;75(2):196-201.

5. Dou J, Ma X, Fang Q, et al. Relationship between serum osteocalcin levels and non-alcoholic fatty liver disease in Chinese men.  Clin Exp Pharmacol Physiol. 2013;40(4):282-288.

6. Liu DM, Guo XZ, Tong HJ, et al. Association between osteocalcin and glucose metabolism: a meta-analysis. Osteoporos Int. 2015;26(12):2823-2833.

7. Mosialou I, Shikhel S, Liu JM, et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2.  Nature. 2017;543(7645):385-390.

8. Paton CM, Rogowski MP, Kozimor AL, Stevenson JL, Chang H, Cooper JA. Lipocalin-2 increases fat oxidation in vitro and is correlated with energy expenditure in normal weight but not obese women. Obesity (Silver Spring). 2013;21(12):e640-e648.

9. Zeng J, Jiang Y, Xiang S, Chen B. Serum bone morphogenetic protein 7, insulin resistance, and insulin secretion in non-diabetic individuals. Diabetes Res Clin Pract. 2011;93(1):e21-e24.