Association between Growth Differentiation Factor 15 (GDF15) and Cardiovascular Risk in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

Shin, Min Young; Kim, Ji Min; Kang, Yea Eun; Kim, Min Kyeong; Joung, Kyong Hye; Lee, Ju Hee; Kim, Koon Soon; Kim, Hyun Jin; Ku, Bon Jeong; Shong, Minho

doi:10.3346/jkms.2016.31.9.1413

Cited by 53 publications

(46 citation statements)

References 23 publications

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“…Whether GDF-15 could be involved as the protector from atherosclerotic injury with similar molecular mechanisms as mentioned above is not sufficiently clear. Although some scientists reported that levels of GDF-15 in people with diabetes demonstrated the close positive association with traditional CV risk factors, such as LDL cholesterol, BMI, age, inflammatory activity, but not with TG [14,15]. The results of our study well correspond with these findings, and we yielded that GDF-15 could be a component of the endogenous vascular repair system that maintains vascular integrity and function.…”

Section: Discussionsupporting

confidence: 87%

Association of growth-differentiation factor-15 with the number of circulating proangiogenic endothelial progenitor cells in patients with type 2 diabetes mellitus

et al. 2018

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The objective: to investigate the relationship between levels of growth differentiation factor-15 (GDF-15) and circulating number of endothelial progenitor cells (EPCs) with angiopoietin phenotypes: CD34+CD14+CD309+, and CD34+CD14+CD309+Tie2+ in patients with type 2 DM. Methods: The study was retrospectively involved 76 patients with type 2 DM aged 38 to 55 years and 30 healthy volunteers. Data collection included demographic and anthropometric information, hemodynamic performances and biomarkers of the diseases. Flow cytometry was used to determine EPCs' populations. Results: The levels of GDF-15 in peripheral blood of diabetics associated with age (r = 0.31, P = 0.044), high-sensitive C-reactive protein [hs-CRP] (r = 0.40, P = 0.001), smoking (r = 0.38, P = 0.001), body mass index [BMI] (r = 0.34, P = 0.001), LDL cholesterol (r = 0.28, P = 0.001), glycated hemoglobin [HbA1c] (r = -0.28, P = 0.001), number of CV risk factors (r = 0.26, P = 0.001). In univariate logistic regression analysis we found that level of GDF-15 ≥ 618 pg/mL, hs-CRP ≥7.12 mg/L, HbA1c ≥6.4%, fasting glucose ≥6.7 mmol/L, and BMI ≥27.3 kg/m2 predicted deficiency of both angiopoetic phenotypes of EPCs. In multivariate logistic regression model GDF-15 ≥618 pg/mL demonstrated the best odds ratio values for declining of EPCs in diabetics in comparison with other predictors including BMI, HbA1c and hs-CRP. Conclusion: GDF-15 was remarkably evaluated in type 2 DM population to healthy volunteers, and it was an independent factor that contributes to mobilization and probably proliferation of endothelial precursors with high angiopoetic activity. Abstract

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Section: Discussionsupporting

confidence: 87%

Association of growth-differentiation factor-15 with the number of circulating proangiogenic endothelial progenitor cells in patients with type 2 diabetes mellitus

et al. 2018

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“…Elevated FGF21 and GDF15 are associated with diabetes and glucose intolerance (18,19) but have been shown to reduce serum glucose and insulin levels (20). Elevated FGF21 can act non-cell autonomously to induce uncoupling protein 1 (UCP1) in brown adipose tissue (BAT), resulting in increased mitochondrial oxidation of lipids (21).…”

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confidence: 99%

Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

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Derbeneva

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Diabetes is associated with impaired glucose metabolism in the presence of excess insulin. Glucose and fatty acids provide reducing equivalents to mitochondria to generate energy, and studies have reported mitochondrial dysfunction in type II diabetes patients. If mitochondrial dysfunction can cause diabetes, then we hypothesized that increased mitochondrial metabolism should render animals resistant to diabetes. This was confirmed in mice in which the heart-muscle-brain adenine nucleotide translocator isoform 1 (ANT1) was inactivated. ANT1-deficient animals are insulin-hypersensitive, glucose-tolerant, and resistant to high fat diet (HFD)-induced toxicity. In ANT1-deficient skeletal muscle, mitochondrial gene expression is induced in association with the hyperproliferation of mitochondria. The ANT1-deficient muscle mitochondria produce excess reactive oxygen species (ROS) and are partially uncoupled. Hence, the muscle respiration under nonphosphorylating conditions is increased. Muscle transcriptome analysis revealed the induction of mitochondrial biogenesis, down-regulation of diabetes-related genes, and increased expression of the genes encoding the myokines FGF21 and GDF15. However, FGF21 was not elevated in serum, and FGF21 and UCP1 mRNAs were not induced in liver or brown adipose tissue (BAT). Hence, increased oxidation of dietary-reducing equivalents by elevated muscle mitochondrial respiration appears to be the mechanism by which ANT1-deficient mice prevent diabetes, demonstrating that the rate of mitochondrial oxidation of calories is important in the etiology of metabolic disease. mitochondria | skeletal muscle | ANT1 | insulin sensitivity

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“…As expected, circulating GDF15 levels have also been shown to help identify and predict cardiovascular disease risk in patients with diabetes [16,38,39]. In a study with newly diagnosed T2DM patients, Shin et al [16] used the Framingham risk score and the New Pooled Cohort Equation score to estimate the 10-year risk of atherosclerotic cardiovascular disease. After adjusting for traditional risk factors, GDF15 was significantly positively correlated with both the Framingham risk score and the New Pooled Cohort Equation score, indicating that the levels of GDF15 may be a useful predictive biomarker of cardiovascular risk in newly Fig.…”

Section: Discussionmentioning

confidence: 90%

“…In diabetic patients, higher levels of lipids and chronic inflammation may directly damage the cardiovascular system [37]. As expected, circulating GDF15 levels have also been shown to help identify and predict cardiovascular disease risk in patients with diabetes [16,38,39]. In a study with newly diagnosed T2DM patients, Shin et al [16] used the Framingham risk score and the New Pooled Cohort Equation score to estimate the 10-year risk of atherosclerotic cardiovascular disease.…”

Section: Discussionmentioning

confidence: 96%

“…Furthermore, diabetes was observed to be independently associated with an increased risk of LEAD, depending on the severity of cardiovascular diseases [13]. Nevertheless, most previous related studies have focused on circulating GDF15 levels and myocardial or coronary artery diseases in patients with diabetes [14][15][16], and the relationship between GDF15 and LEAD has been less explored.…”

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confidence: 99%

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The association between serum growth differentiation factor 15 levels and lower extremity atherosclerotic disease is independent of body mass index in type 2 diabetes

et al. 2020

Cardiovasc Diabetol

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Background: Clinical and basic investigations have indicated a significant association between circulating growth differentiation factor 15 (GDF15) and cardiovascular disease; however, the relationship between GDF15 and lower extremity atherosclerotic disease (LEAD) has been less studied. The present study aimed to explore the association between GDF15 and LEAD in Chinese patients with type 2 diabetes mellitus (T2DM). Considering that obesity is an important factor associated with circulating GDF15 levels, whether the relationship between serum GDF15 levels and LEAD is affected by body mass index (BMI) was also analysed.Methods: A total of 376 hospitalized T2DM patients were enrolled (161 with LEAD and 215 without LEAD). A sandwich enzyme-linked immunosorbent assay was used to detect the serum GDF15 levels. The femoral intima-media thickness (F-IMT) and LEAD were assessed by ultrasonography.Results: Patients with LEAD had significantly higher serum GDF15 levels than those without LEAD, regardless of whether their BMI was < 25 kg/m 2 or ≥ 25 kg/m 2 (both P < 0.05). Serum GDF15 levels were independently positively related to the F-IMT (standardized β = 0.162, P = 0.002). After adjusting for confounding factors, per 1-standard deviation (SD) increase in the serum GDF15 levels was significantly related to an approximately 1.4-fold increased risk of LEAD in the total population (P < 0.05). Regardless of whether the BMI was < 25 kg/m 2 or ≥ 25 kg/m 2 , this association remained significant, with approximately 1.6-and 1.4-fold increased risks of LEAD, respectively (both P < 0.05). Conclusions: High serum GDF15 levels were significantly correlated with an increased risk of LEAD in T2DM patients, and this relationship was independent of BMI.

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Association between Growth Differentiation Factor 15 (GDF15) and Cardiovascular Risk in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

Cited by 53 publications

References 23 publications

Association of growth-differentiation factor-15 with the number of circulating proangiogenic endothelial progenitor cells in patients with type 2 diabetes mellitus

Association of growth-differentiation factor-15 with the number of circulating proangiogenic endothelial progenitor cells in patients with type 2 diabetes mellitus

Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

The association between serum growth differentiation factor 15 levels and lower extremity atherosclerotic disease is independent of body mass index in type 2 diabetes

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