Effect of gamma-carboxylase inhibition on serum osteocalcin may be partially protective against developing diabetic cardiomyopathy in type 2 diabetic rats

Gamal, Sarah; Sadek, Nermeen Bakr; Rashed, Laila Ahmed; Shawky, Heba Mohamed; El-Din, Maha Mohamed Gamal

doi:10.1177/1479164116653239

Cited by 8 publications

(9 citation statements)

References 30 publications

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“…Thus, there is a previously postulated mechanism for warfarin to lower blood glucose. Although warfarin's effects on blood glucose have not been studied in human trials, in diabetic rats, it increases insulin secretion and reduces fasting glucose . Moreover, a positive feedback loop has been postulated in which uncarboxylated osteocalcin stimulates insulin secretion, which further stimulates osteoblasts to produce uncarboxylated osteocalcin, the metabolism of which is inhibited by warfarin .…”

Section: Discussionmentioning

confidence: 99%

“…Although warfarin's effects on blood glucose have not been studied in human trials, 19 in diabetic rats, it increases insulin secretion and reduces fasting glucose. 22 Moreover, a positive feedback loop has been postulated in which uncarboxylated osteocalcin stimulates insulin secretion, which further stimulates osteoblasts to produce uncarboxylated osteocalcin, the metabolism of which is inhibited by warfarin. 19 Such a positive feedback loop would be expected to result in a more marked hypoglycemic effect of warfarin after prolonged exposure, as is seen in Figure 1.…”

Section: Discussionmentioning

confidence: 99%

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Serious Hypoglycemia and Use of Warfarin in Combination With Sulfonylureas or Metformin

Nam

Brensinger

Bilker

et al. 2018

Clin Pharma and Therapeutics

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Prior research suggests that warfarin, when given concomitantly with some sulfonylureas, may increase the risk of serious hypoglycemia. However, the clinical significance remains unclear. We examined rate ratios (RRs) for the association between serious hypoglycemia and concomitant use of warfarin with either sulfonylureas or metformin using a self-controlled case series design and US Medicaid claims (supplemented with Medicare claims) from 1999 to 2011. Across all risk windows combined, warfarin was associated with an elevated rate of serious hypoglycemia when given concomitantly with glimepiride (RR, 1.47; 95% confidence interval (CI), 1.07-2.02) and metformin (RR, 1.73; 95% CI, 1.38-2.16). Particularly in the late risk window (>120 days since beginning concomitancy), most of the RRs for warfarin were elevated: glipizide (RR, 1.72; 95% CI, 1.29-2.29), glyburide (RR, 1.57; 95% CI, 1.15-2.15), metformin (RR, 2.26; 95% CI, 1.67-3.05), and glimepiride (RR, 1.56; 95% CI, 0.97-2.50). These results are consistent with a previously hypothesized hypoglycemic effect of warfarin in patients with type 2 diabetes through inhibition of the carboxylation of osteocalcin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serious Hypoglycemia and Use of Warfarin in Combination With Sulfonylureas or Metformin

Nam

Brensinger

Bilker

et al. 2018

Clin Pharma and Therapeutics

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“…17 Osteocalcin could exert a protective effect on cardiovascular risk in diabetic patients by improving glucose tolerance and hyperlipidaemia. [18][19][20] While our previous studies have illustrated the antioxidative and antiapoptotic role of undercarboxylated osteocalcin (ucOC) in protecting the diabetic heart from developing DCM, 18 the present study is the first, to the best of our knowledge, to investigate the potential role of ucOC as a therapeutic agent for DCM and to document the relationships among increased ucOC, upregulation of VEGF expression, improvement in myocardial microcirculation, and its subsequent cardiac functional and histopathological changes.…”

Section: Introductionmentioning

confidence: 84%

The Potential Role of Undercarboxylated Osteocalcin Upregulation in Microvascular Insufficiency in a Rat Model of Diabetic Cardiomyopathy

Sadek

Gamal

Aboulhoda

et al. 2019

J Cardiovasc Pharmacol Ther

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Background: Diabetic cardiomyopathy (DCM) is accompanied by microvascular complications that lead to myocardial dysfunction and heart failure. Most conventional therapies cannot ameliorate the microvascular insufficiency in DCM. In this study, we tested the hypothesis that undercarboxylated osteocalcin (ucOC) may be a new adjuvant therapy against the progression of DCM and its underlying microvascular pathology. Materials and Methods: Diabetes was induced in Wistar rats with a high-fat diet combined with streptozotocin injections, and ucOC was upregulated after warfarin administration in the treated group. After 8 weeks, cardiac functions were assessed using a Langendorff apparatus. Cardiac tissue samples were also extracted to assess the ucOC receptor and vascular endothelial growth factor (VEGF) for histopathological studies. Results: Both the systolic and the diastolic dysfunction observed in the DCM group were significantly improved after the increase in ucOC blood levels. Significant improvement in VEGF and CD31 expression after warfarin injection was associated with increased capillary density, neovascularization, and decreased myocardial fibrosis together with the reestablishment of myocardial structural and ultrastructural patterns. Conclusion: Undercarboxylated osteocalcin may have a promising effect in improving microvascular insufficiency and myocardial dysfunction in DCM.

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“…Serum osteocalcin may play an important role in protecting myocardial cells by binding with the GPRC6A receptor. The mechanism of the protection against cardiomyopathy mediated by osteocalcin in mice with type 2 diabetes was studied by Gamal et al [27]. These authors found that serum osteocalcin levels and serum adiponectin levels in the diabetes group were much lower than the levels in the control group.…”

Section: Discussionmentioning

confidence: 99%

Low serum osteocalcin levels are correlated with left ventricular systolic dysfunction and cardiac death in Chinese men

Zhang

Shen

et al. 2018

Acta Pharmacol Sin

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Osteocalcin is a newly identified type of cytokine secreted by osteoblasts, which has an endocrine function, mediates energy and glycol-lipid metabolism, and is closely related to cardiovascular diseases. In this study, we investigated the value of serum osteocalcin levels in predicting left ventricular systolic dysfunction and cardiac death. A total of 258 patients in the Department of Cardiology were included. Two-dimensional echocardiography was performed in all the subjects. The cardiac death of subjects occurring with a median follow-up of 4.6 years was informed via phone calls or the electronic medical records. The serum osteocalcin levels were measured using electrochemiluminescent immunoassay. We found that the median left ventricular ejection fractions (LVEFs) were 62% in men and 63% in women. In the men with a LVEF > 62%, the serum osteocalcin levels were significantly higher than in those with LVEF ≤ 62% (P = 0.042), whereas this difference was absent in the women. Both the serum osteocalcin (β = 0.095, P = 0.028) and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP; β = -0.003, P < 0.01) levels remained independently significantly correlated with LVEF in the men but not in the women. Receiver operating characteristic (ROC) analyses of the men revealed that the serum osteocalcin (P = 0.007), serum NT-pro-BNP (P = 0.018) and serum osteocalcin + NT-pro-BNP (P < 0.01) levels were all significant in identifying left ventricular systolic dysfunction at baseline, but the pairwise comparisons of the three areas under the curves (AUCs) were all non-significant. The men in the lower osteocalcin level group at baseline suffered a greater risk of future cardiac death than those in the higher osteocalcin level group, whereas the result for NT-pro-BNP exhibited the opposite pattern. In conclusion, lower serum osteocalcin levels in the men could identify left ventricular systolic dysfunction and cardiac death in a manner that was not inferior to high serum NT-pro-BNP levels.

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Effect of gamma-carboxylase inhibition on serum osteocalcin may be partially protective against developing diabetic cardiomyopathy in type 2 diabetic rats

Cited by 8 publications

References 30 publications

Serious Hypoglycemia and Use of Warfarin in Combination With Sulfonylureas or Metformin

Serious Hypoglycemia and Use of Warfarin in Combination With Sulfonylureas or Metformin

The Potential Role of Undercarboxylated Osteocalcin Upregulation in Microvascular Insufficiency in a Rat Model of Diabetic Cardiomyopathy

Low serum osteocalcin levels are correlated with left ventricular systolic dysfunction and cardiac death in Chinese men

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