Betatrophin Abstracts 1

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β-Cell dysfunction in diabetes: a crisis of identity
            (Brereton et al., 2016)  Download
Type 2 diabetes is characterized by insulin resistance and a progressive loss of β-cell function induced by a combination of both β-cell loss and impaired insulin secretion from remaining β-cells. Here, we review the fate of the β-cell under chronic hyperglycaemic conditions with regard to β-cell mass, gene expression, hormone content, secretory capacity and the ability to de- or transdifferentiate into other cell types. We compare data from various in vivo and in vitro models of diabetes with a novel mouse model of inducible, reversible hyperglycaemia (βV59M mice). We suggest that insulin staining using standard histological methods may not always provide an accurate estimation of β-cell mass or number. We consider how β-cell identity is best defined, and whether expression of transcription factors normally found in islet progenitor cells, or in α-cells, implies that mature β-cells have undergone dedifferentiation or transdifferentiation. We propose that even in long-standing diabetes, β-cells predominantly remain β-cells-but not as we know them.

Vitamin D modifies the associations between circulating betatrophin and cardiometabolic risk factors among youths at risk for metabolic syndrome.
            (Fu et al., 2016)  Download
BACKGROUND:  Betatrophin has been recently reported to play a role in glucose homeostasis by inducing beta-cell proliferation in mice. However, studies in human are inconsistent. As a nutritionally-regulated liver-enriched factor, we hypothesize that betatrophin might be regulated by vitamin D, and ignorance of vitamin D status may explain the discrepancy in previous human studies. The aims of this study were to assess the association between circulating betatrophin and glucose homeostasis as well as other cardiometabolic variables in a cohort of youths at risk for metabolic syndrome and test the possible influence of vitamin D status on the association. METHODS:  559 subjects aged 14-28 years were recruited from Beijing children and adolescents metabolic syndrome study. All underwent a 2 h-oral glucose tolerance test. Serum levels of betatrophin, 25-hydroxy-vitamin D as well as adipokines including adiponectin and fibroblast growth factor 21 (FGF21) were measured by immunoassays. The relationships between betatrophin and insulin resistance, beta-cell function, other cardiometabolic variables and vitamin D status were evaluated. RESULTS:  Participants in the highest quartile of betatrophin levels had the highest levels of total cholesterol (P < 0.001), triglyceride (P < 0.001) and low-density lipoprotein cholesterol (P < 0.001) and the lowest levels of vitamin D (P = 0.003). After stratification by vitamin D status, betatrophin in subjects with vitamin D deficiency were positively correlated with unfavorable metabolic profiles including high blood pressures, dyslipidemia and hyperglycemia, whereas betatrophin in those with higher vitamin D levels only showed negative association with fasting insulin, 2 h-insulin, and insulin resistance. In addition, adiponectin and FGF21 demonstrated the expected associations with metabolic parameters. CONCLUSIONS:  Elevated betatrophin levels were associated with cardiometabolic risk factors in this young population, but the association was largely dependent on vitamin D status. These findings may provide valuable insights in the regulation of betatrophin and help explain the observed discrepancies in literature.

Circulating Betatrophin Is Increased in Patients with Overt and Subclinical Hypothyroidism.
            (Han et al., 2016)  Download
Thyroid hormone (TH) affects many metabolic processes such as promoting oxidation of sugar, fat, and protein in many tissues. Thyroid dysfunction is associated with metabolic disorders. The newly discovered adipocyte- and hepatocyte-derived cytokine, betatrophin, has been reported to be involved in metabolic diseases, but its influence on thyroid dysfunction is uncertain. Therefore, the present study aims to evaluate circulating betatrophin levels in subjects with different thyroid function status and to predict the factors associated with betatrophin levels, especially whether thyroid stimulating hormone (TSH), TH, or thyroid autoantibodies are associated with betatrophin levels. In the study, serum betatrophin was measured in the subjects grouped as overt hypothyroidism (OH), subclinical hypothyroidism (SCH), euthyroid with isolated thyroid peroxidase antibody positivity (isolated Ab), and healthy control (HC), according to their thyroid functions. From our results, we found that betatrophin may be associated with thyroid insufficiency but not thyroid autoimmunity. Thus, when interpreting the results of betatrophin, thyroid functions should also be taken into consideration.

Diabetes: Betatrophin-inducing beta-cell expansion to treat diabetes mellitus?
            (Kugelberg, 2013) Download
Betatrophin, a newly identified hormone, increases the production and expansion of insulin-secreting β cells in mice, research from Harvard University suggests.


The p38-PGC-1α-irisin-betatrophin axis: Exploring new pathways in insulin resistance.
            (Sanchis-Gomar and Perez-Quilis, 2014)  Download
The discovery of irisin as a novel and promising peptidic hormone has raised hopes regarding the hypothesis that irisin may provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions since this hormone may prove to be therapeutically and clinically beneficial. In addition, a new hormone, betatrophin, has recently been identified by Yi and coworkers. Both hormones are connected by a new pathway clearly involved in insulin resistance. We hypothesize here how these hormones may be linked and their possible implications in both aged-reduced restricted regenerative capacity and dedifferentiated β cells of diabetic patients.

Correlation between Bethatrophin and 25(OH)D Concentrations in a Group of Subjects With Normal and Impaired Glucose Metabolism.
            (Turkon et al., 2016)  Download
Aim: Inducing beta cell replication is a potential therapeutic approach for the treatment of diabetes mellitus. Recently betatrophin was suggested as a novel stimulator of beta cell proliferation in mice but its role in humans remains to be established. We aimed to investigate betatrophin concentration and its association with metabolic parameters in a group of individuals with normal glucose tolerance, pre-diabetes and diabetes mellitus who had not been previously treated. Methods: A total of 72 subjects were recruited for this cross sectional study: 23 subjects with normal glucose tolerance (NGT), 22 subjects with prediabetes, and 27 subjects with diabetes mellitus (DM). Circulating betatrophin concentration, 75 g oral glucose tolerance test, fasting insulin, glycosylated hemoglobin, 25hydroxy vitamin D and HOMA IR were measured. Results: The difference in betatrophin values did not reach statistical significance between the 3 groups [NGT:206 (176-297)pg/mL, Prediabetes:232 (181-254)pg/mL, DM:245 (205-526)pg/mL, p=0.078]. Betatrophin was negatively significantly correlated with BMI and positively significantly correlated with 25(OH)vitD (p=0.043 and p=0.001 respectively). Multivariate linear regression showed that 25(OH) vitD (β=0.440 p=0.001) and fasting glucose (β=0.003 p=0.038) were variables associated with betatrophin concentration (R2=0.251). Conclusions: In a group of subjects ranging from those with normal glucose tolerance to newly diagnosed diabetes, we found that 25(OH)D and fasting glucose were factors associated with serum betatrophin concentration.


Betatrophin: a hormone that controls pancreatic beta cell proliferation
            (Yi et al., 2013) Download
Replenishing insulin-producing pancreatic beta cell mass will benefit both type I and type II diabetics. In adults, pancreatic beta cells are generated primarily by self-duplication. We report on a mouse model of insulin resistance that induces dramatic pancreatic beta cell proliferation and beta cell mass expansion. Using this model, we identify a hormone, betatrophin, that is primarily expressed in liver and fat. Expression of betatrophin correlates with beta cell proliferation in other mouse models of insulin resistance and during gestation. Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic beta cell proliferation, expands beta cell mass, and improves glucose tolerance. Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.

 


References

Brereton, MF, M Rohm, and FM Ashcroft (2016), ‘β-Cell dysfunction in diabetes: a crisis of identity’, Diabetes Obes Metab, 18 Suppl 1 102-9. PubMed: 27615138
Fu, J, et al. (2016), ‘Vitamin D modifies the associations between circulating betatrophin and cardiometabolic risk factors among youths at risk for metabolic syndrome.’, Cardiovasc Diabetol, 15 (1), 142. PubMed: 27716289
Han, C, et al. (2016), ‘Circulating Betatrophin Is Increased in Patients with Overt and Subclinical Hypothyroidism.’, Biomed Res Int, 2016 5090852. PubMed: 27213151
Kugelberg, E. (2013), ‘Diabetes: Betatrophin-inducing beta-cell expansion to treat diabetes mellitus?’, Nat Rev Endocrinol, 9 (7), 379. PubMed: 23648871
Sanchis-Gomar, F and C Perez-Quilis (2014), ‘The p38-PGC-1α-irisin-betatrophin axis: Exploring new pathways in insulin resistance.’, Adipocyte, 3 (1), 67-68. PubMed: 24575373
Turkon, H, et al. (2016), ‘Correlation between Bethatrophin and 25(OH)D Concentrations in a Group of Subjects With Normal and Impaired Glucose Metabolism.’, Exp Clin Endocrinol Diabetes, PubMed: 26910534
Yi, P., J. S. Park, and D. A. Melton (2013), ‘Betatrophin: a hormone that controls pancreatic beta cell proliferation’, Cell, 153 (4), 747-58. PubMed: 23623304