Diabetes & Metabolism Journal

Review

Metabolic Risk/Epidemiology
One-Carbon Metabolism Nutrients, Genetic Variation, and Diabetes Mellitus: Jie Zhu, Gunjana Saikia, Xiaotao Zhang, Xiaoxi Shen, Ka Kahe; Diabetes Metab J. 2024;48(2):170-183. Published online March 12, 2024; DOI: https://doi.org/10.4093/dmj.2023.0272

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Diabetes mellitus (DM) affects about 9.3% of the population globally. Hyperhomocysteinemia (HHcy) has been implicated in the pathogenesis of DM, owing to its promotion of oxidative stress, β-cell dysfunction, and insulin resistance. HHcy can result from low status of one-carbon metabolism (OCM) nutrients (e.g., folate, choline, betaine, vitamin B6, B12), which work together to degrade homocysteine by methylation. The etiology of HHcy may also involve genetic variation encoding key enzymes in OCM. This review aimed to provide an overview of the existing literature assessing the link between OCM nutrients status, related genetic factors, and incident DM. We also discussed possible mechanisms underlying the role of OCM in DM development and provided recommendations for future research and practice. Even though the available evidence remains inconsistent, some studies support the potential beneficial effects of intakes or blood levels of OCM nutrients on DM development. Moreover, certain variants in OCM-related genes may influence metabolic handling of methyl-donors and presumably incidental DM. Future studies are warranted to establish the causal inference between OCM and DM and examine the interaction of OCM nutrients and genetic factors with DM development, which will inform the personalized recommendations for OCM nutrients intakes on DM prevention.

Citations

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Alterations in Choline Metabolism in Non-Obese Individuals with Insulin Resistance and Type 2 Diabetes Mellitus
Haya Al-Sulaiti, Najeha Anwardeen, Sara S. Bashraheel, Khaled Naja, Mohamed A. Elrayess
Metabolites.2024; 14(8): 457. CrossRef
Association between oxidative balance score and diabetic kidney disease, low estimated glomerular filtration rate and albuminuria in type 2 diabetes mellitus patients: a cross-sectional study
Cong Liu, Jiju Yang, Hongdian Li, Yuanyuan Deng, Pengfei He, Jiao Zhang, Mianzhi Zhang
Frontiers in Endocrinology.2024;[Epub] CrossRef

Original Articles

The Relationship among Homocysteine, Bilirubin, and Diabetic Retinopathy: Ho Chan Cho; Diabetes Metab J. 2011;35(6):595-601. Published online December 26, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.6.595

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Background

Diabetic retinopathy is a common microvascular complication of diabetes mellitus (DM) and the leading cause of blindness in adults. Homocysteine, a risk factor with toxic effects on vascular endothelial cells, and bilirubin, a protectant with antioxidant and anti-inflammatory properties on the vasculature, have been reported to be linked to vaso-occlusive disorders. Therefore, the author of the present study investigated the association between the levels of plasma homocysteine and serum total bilirubin and the incidence of diabetic retinopathy as a chronic microvascular complication in patients with type 2 diabetes mellitus (T2DM).

Methods

A total of 102 patients with T2DM who visited our hospital from January 2009 to January 2010 were assessed.

Results

Of the 102 patients, the prevalence of diabetic retinopathy was 67 cases (65.7%) according to clinical ophthalmic examination. The duration of DM (P<0.001), age (P=0.003), fasting blood glucose (P=0.045) and urine albumin-creatinine ratio (P=0.015) in univariate analysis and plasma homocysteine level (P=0.038), duration of DM (P=0.001), and total bilirubin level (P=0.012) in multiple logistic regression analysis were statistically significantly associated with the incidence of diabetic retinopathy.

Conclusion

The present study indicates that homocysteine and bilirubin may be useful biomarkers for increased risk of diabetic retinopathy since retinopathy in patients with T2DM was linked to higher plasma homocysteine level and decreased serum total bilirubin level.

Citations

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Role of hyperhomocysteinemia in the progression of diabetic retinopathy
Pooja H V, Lakshmi M S
Indian Journal of Clinical and Experimental Ophthalmology.2024; 10(1): 160. CrossRef
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Dima Samer Ali, Samuel O. Sofela, Muhammedin Deliorman, Pavithra Sukumar, Ma-sum Abdulhamid, Sherifa Yakubu, Ciara Rooney, Ryan Garrod, Anoop Menachery, Rabih Hijazi, Hussein Saadi, Mohammad A. Qasaimeh
Lab on a Chip.2024; 24(11): 2906. CrossRef
Serum Total Bilirubin and Oxidative Stress Status in Diabetic Retinopathy – A Hospital-Based Observational Study
Prabhavathi K, Mamatha Kunder, Shashidhar K.N, Kanthamani K, Raveesha A
Biomedical and Pharmacology Journal.2024; 17(2): 1317. CrossRef
Plasma homocysteine is associated with nonproliferative retinopathy in patients with type 2 diabetes without renal disease
Martina Tomić, Romano Vrabec, Spomenka Ljubić, Tomislav Bulum, Dario Rahelić
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Blood Viscosity in Subjects With Type 2 Diabetes Mellitus: Roles of Hyperglycemia and Elevated Plasma Fibrinogen
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Yang Huang, Jinglan Li, Wenzhe Li, Nanping Ai, Haiying Jin, Recep Liman
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Homocysteine and diabetes: Role in macrovascular and microvascular complications
Emir Muzurović, Ivana Kraljević, Mirsala Solak, Siniša Dragnić, Dimitri P. Mikhailidis
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Quantifying Fibrinogen-Dependent Aggregation of Red Blood Cells in Type 2 Diabetes Mellitus
Yixiang Deng, Dimitrios P. Papageorgiou, Xuejin Li, Nikolaos Perakakis, Christos S. Mantzoros, Ming Dao, George Em Karniadakis
Biophysical Journal.2020; 119(5): 900. CrossRef
Effect of folic acid supplementation on nerve conduction velocity in diabetic polyneuropathy patients
Tayebeh Mottaghi, Fariborz Khorvash, Mohammadreza Maracy, Nick Bellissimo, Gholamreza Askari
Neurological Research.2019; 41(4): 364. CrossRef
Association between serum total bilirubin levels and the risk of type 2 diabetes mellitus
Min Yang, Changlin Ni, Baocheng Chang, Zhenhuan Jiang, Yanjuan Zhu, Yunzhao Tang, Zhu Li, Chenguang Li, Bin Li
Diabetes Research and Clinical Practice.2019; 152: 23. CrossRef
Elevated Serum Total Bilirubin Concentrations Are Negatively Associated with Diabetic Retinopathy among the Chinese Northeastern Population
Dan Zhang, Wei Zhang, Shi Jin, Wei Wang, Dan Guo, Lu Wang
International Journal of Endocrinology.2018; 2018: 1. CrossRef
Serum bilirubin levels are negatively associated with diabetic retinopathy in patients with type 1 diabetes and normal renal function
Tomislav Bulum, Martina Tomić, Lea Duvnjak
International Ophthalmology.2018; 38(3): 1095. CrossRef
The Association between Serum Bilirubin Level and Electrochemical Skin Conductance in Chinese Patients with Type 2 Diabetes
Fei Mao, Xiaoming Zhu, Bin Lu, Yiming Li
International Journal of Endocrinology.2018; 2018: 1. CrossRef
Evaluation of kidney function and risk factors of retinopathy in Type 2 diabetes mellitus people in South Africa
F.A. Ganjifrockwala, J.T. Joseph, G. George
Diabetes Research and Clinical Practice.2017; 127: 218. CrossRef
Homocysteine and Its Relationship to Asymptomatic Carotid Stenosis in a Chinese Community Population
Jiaokun Jia, Anxin Wang, Jing Wang, Jianwei Wu, Xiujuan Yan, Yong Zhou, Shengyun Chen, Xingquan Zhao
Scientific Reports.2016;[Epub] CrossRef
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Silvia Gazzin, Libor Vitek, Jon Watchko, Steven M. Shapiro, Claudio Tiribelli
Trends in Molecular Medicine.2016; 22(9): 758. CrossRef
The Negative Relationship between Bilirubin Level and Diabetic Retinopathy: A Meta-Analysis
Bo Zhu, Xiaomei Wu, Kang Ning, Feng Jiang, Lu Zhang, Demetrios G. Vavvas
PLOS ONE.2016; 11(8): e0161649. CrossRef
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Olga Simó-Servat, Rafael Simó, Cristina Hernández
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Serum total bilirubin concentration is negatively associated with increasing severity of retinopathy in patients with type 2 diabetes mellitus
Risa Sekioka, Masami Tanaka, Takeshi Nishimura, Hiroshi Itoh
Journal of Diabetes and its Complications.2015; 29(2): 218. CrossRef
Plasma Homocysteine is Associated with Retinopathy in Type 1 Diabetic Patients in the Absence of Nephropathy
Tomislav Bulum, Kristina Blaslov, Lea Duvnjak
Seminars in Ophthalmology.2014; : 1. CrossRef
Relationship between homocysteine level and diabetic retinopathy: a systematic review and meta-analysis
Chong Xu, Yan Wu, Guodong Liu, Xiaoqiang Liu, Fang Wang, Jing Yu
Diagnostic Pathology.2014;[Epub] CrossRef
Alterations of Retinal Vasculature in Cystathionine–β-Synthase Heterozygous Mice
Amany Tawfik, Shanu Markand, Mohamed Al-Shabrawey, Jamie N. Mayo, Jason Reynolds, Shawn E. Bearden, Vadivel Ganapathy, Sylvia B. Smith
The American Journal of Pathology.2014; 184(9): 2573. CrossRef
Decreased Serum Bilirubin Is Associated With Silent Cerebral Infarction
Rui-Yan Li, Zhi-Gang Cao, Ji-Rong Zhang, Ying Li, Rui-Tao Wang
Arteriosclerosis, Thrombosis, and Vascular Biology.2014; 34(4): 946. CrossRef
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Nihon Kyukyu Igakukai Zasshi.2014; 25(6): 239. CrossRef
Serum total bilirubin levels and prevalence of diabetic retinopathy in a Chinese population (中国人群血清总胆红素水平与糖尿病视网膜病变相关性的研究)
Syeda Sadia Najam, Jichao Sun, Jie Zhang, Min Xu, Jieli Lu, Kan Sun, Mian Li, Tiange Wang, Yufang Bi, Guang Ning
Journal of Diabetes.2014; 6(3): 221. CrossRef
Omentin changes following bariatric surgery and predictive links with biomarkers for risk of cardiovascular disease
Marc Lapointe, Paul Poirier, Julie Martin, Marjorie Bastien, Audrey Auclair, Katherine Cianflone
Cardiovascular Diabetology.2014;[Epub] CrossRef
Homocysteine Serum Levels in Diabetic Patients with Non Proliferative, Proliferative and without Retinopathy
Giulia Malaguarnera, Caterina Gagliano, Maria Giordano, Salvatore Salomone, Marco Vacante, Claudio Bucolo, Filippo Caraci, Michele Reibaldi, Filippo Drago, Teresio Avitabile, Massimo Motta
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Mechanisms of Diabetic Complications
Josephine M. Forbes, Mark E. Cooper
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Homocysteine as a Risk Factor for Development of Microalbuminuria in Type 2 Diabetes: Eun-Hee Cho, Eun Hee Kim, Won Gu Kim, Eun Hui Jeong, Eun Hee Koh, Woo-Je Lee, Min-Seon Kim, Joong-Yeol Park, Ki-Up Lee; Korean Diabetes J. 2010;34(3):200-206. Published online June 30, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.3.200

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Background

Kidney function is critical in homocysteine clearance, and plasma homocysteine level is frequently increased in patients with renal failure. On the other hand, recent studies in animals have shown that hyperhomocysteinemia induces renal injury. In this study, we determined whether hyperhomocysteinemia can be a risk factor for the development of microalbuminuria in patients with type 2 diabetes.

Methods

A nested case-control study. Of 887 patients with type 2 diabetes who did not have microalbuminuria at baseline, 76 developed microalbuminuria during follow-up (mean, 36.0 ± 11.7 months; range, 18 to 76 months). The control group consisted of 152 age- and sex-matched subjects who did not develop microalbuminuria. Baseline plasma homocysteine concentrations were measured in stored samples.

Results

Baseline plasma homocysteine concentrations and mean HbA1C levels during follow-up were significantly higher in patients who developed microalbuminuria than in those who remained normoalbuminuric. Multivariate logistic regression analysis showed that baseline plasma homocysteine level and mean HbA1C were independent predictors of microalbuminuria in type 2 diabetes.

Conclusion

Hyperhomocysteinemia was associated with increased risk of microalbuminuria in patients with type 2 diabetes supporting the concept that hyperhomocysteinemia has an etiologic role in the pathogenesis of diabetic nephropathy.

Citations

Citations to this article as recorded by

Homocysteine and diabetes: Role in macrovascular and microvascular complications
Emir Muzurović, Ivana Kraljević, Mirsala Solak, Siniša Dragnić, Dimitri P. Mikhailidis
Journal of Diabetes and its Complications.2021; 35(3): 107834. CrossRef
Associations of Homocysteine with B Vitamins and Zinc in Serum Levels of Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study
Sadako MATSUI, Chika HIRAISHI, Ryo SATO, Takai KOJIMA, Kiyotaka ANDO, Kei FUJIMOTO, Hiroshi YOSHIDA
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A risk scoring system for the decreased glomerular filtration rate in Chinese general population
Yan Gu, Min Chen, Bei Zhu, Xiaohua Pei, Zhenzhu Yong, Xiaona Li, Qun Zhang, Weihong Zhao
Journal of Clinical Laboratory Analysis.2020;[Epub] CrossRef
Relationship between plasma total homocysteine and the severity of renal function in Chinese patients with type 2 diabetes mellitus aged ≥75 years
Ning Ma, Ning Xu, Dong Yin, Weiwei Liu, Mengping Wu, Xingbo Cheng
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Correlation between serum homocysteine level and ulcerative colitis: A meta-analysis
Yifang Zhong, Feng Yan, Weixia Jie, Ying Zhou, Fang Fang
Pteridines.2019; 30(1): 114. CrossRef
The role of molecular genetic alterations in genes involved in folate and homocysteine metabolism in multifactorial diseases pathogenesis
A. M. Burdennyy, V. I. Loginov, T. M. Zavarykina, E. A. Braga, A. A. Kubatiev
Russian Journal of Genetics.2017; 53(5): 528. CrossRef
МОЛЕКУЛЯРНО-ГЕНЕТИЧЕСКИЕ НАРУШЕНИЯ ГЕНОВ ФОЛАТНОГО И ГОМОЦИСТЕИНОВОГО ОБМЕНА В ПАТОГЕНЕЗЕ РЯДА МНОГОФАКТОРНЫХ ЗАБОЛЕВАНИЙ, "Генетика"
А. М. Бурдённый, В.И. Логинов, Т.М. Заварыкина, Э.А. Брага, А.А. Кубатиев
Генетика.2017; (5): 526. CrossRef
Association Between Plasma Homocysteine and Microalbuminuria in Untreated Patients with Essential Hypertension: a Case-Control Study
Ze-min Kuang, Ying Wang, Shu-jun Feng, Long Jiang, Wen-li Cheng
Kidney and Blood Pressure Research.2017; 42(6): 1303. CrossRef
NMDA Receptors as Potential Therapeutic Targets in Diabetic Nephropathy: Increased Renal NMDA Receptor Subunit Expression in Akita Mice and Reduced Nephropathy Following Sustained Treatment With Memantine or MK-801
Hila Roshanravan, Eun Young Kim, Stuart E. Dryer
Diabetes.2016; 65(10): 3139. CrossRef
Association between homocysteine status and the risk of nephropathy in type 2 diabetes mellitus
Song Mao, Wei Xiang, Songming Huang, Aihua Zhang
Clinica Chimica Acta.2014; 431: 206. CrossRef
Prevalence and Determinants of Diabetic Nephropathy in Korea: Korea National Health and Nutrition Examination Survey
Jae Hee Ahn, Ji Hee Yu, Seung-Hyun Ko, Hyuk-Sang Kwon, Dae Jung Kim, Jae Hyeon Kim, Chul Sik Kim, Kee-Ho Song, Jong Chul Won, Soo Lim, Sung Hee Choi, Kyungdo Han, Bong-Yun Cha, Nan Hee Kim
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Satyendra Kumar Sonkar, Gyanendra Kumar Sonkar, Deepika Soni, Dheeraj Soni, Kauser Usman
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Genetic Predisposition for Development of Nephropathy in Type 2 Diabetes Mellitus
Ravindra Kumar, Raj Kumar Sharma, Sarita Agarwal
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Is C677T Polymorphism in Methylenetetrahydrofolate Reductase Gene a Risk Factor for Diabetic Nephropathy or Diabetes Mellitus in a Chinese Population?
Wen-peng Cui, Bing Du, Ye Jia, Wen-hua Zhou, Sheng-mao Liu, Ying-chun Cui, Fu-zhe Ma, Ping Luo, Li-ning Miao
Archives of Medical Research.2012; 43(1): 42. CrossRef
The role of coagulation and inflammation in the development of diabetic nephropathy in patients withdiabetes mellitus type 2
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Relationship between Serum Homocysteine Levels and Vascular Complications in Type 2 Diabetic Patients.: Seung Jin Choi, Jae Taek Kim, Yeon Sahng Oh, Soon Hyun Shinn; Korean Diabetes J. 2002;26(2):112-125. Published online April 1, 2002

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Abstract PDF: BACKGROUND
Chronic complications in type 2 diabetic patients have microvascular and macrovascular components. Previous studies have shown that incidence of macrovascular complications correlates with the serum homocysteine levels, but the relationship is unclear. In addition, the connection between the microvascular complications and the serum homocysteine levels is still obscure and controversial. In this study, the relationship between the serum homocysteine levels and microvascular and macrovascular complications were evaluated in type 2 diabetic patients. METHODS: In 58 type 2 diabetic patients, the serum homocysteine levels, folic acid levels, Vit B12 levels, PAI-1 levels, the standard risk factors for macrovascular complications, the fasting serum glucose levels, the HbA1C levels, and the fasting insulin and C-peptide concentrations, the renal function tests, and the carotid intima-media thickness were measured and the relationship between them and the serum homocysteine level was analyzed according to the presence and absence of macrovascular and microvascular complications. RESULTS: 1) In type 2 diabetic patients, the mean serum homocysteine level was 9.9+/-.2 mol/L. The serum homocysteine level showed no relationship with the clinical and biochemical variables including the risk factors for atherosclerosis except the serum creatinine and creatinine clearance. 2) The maximum, minimum, and mean of the intima- media thickness of right carotid artery were 4.00+/-.20, 0.50+/-.04, 1.04+/-.62 mm, of left carotid artery were 3.54+/-.00, 0.31+/-.02, 1.03+/-.55 mm, and means were 3.77+/-.10, 0.44+/-.03, 1.03+/-.54 mm, and correlated with the serum homocysteine leve l (p=0.03), but only the serum LDL cholesterol level independently correlated with the intima-media thickness (p=0.04). 3) The serum homocysteine level (p=0.01) and intima-media thickness (p<0.01) was significantly higher in type 2 diabetic patients with macrovascular complications than without it. 4) The serum homocysteine level did not correlate with the incidence microvascular complications, but the intima-media thickness did correlate with diabetic nephropathy (p=0.03). CONCLUSIONS: The serum homocysteine level did not correlated with the incidence of diabetic microvascular complications. However, there was a small correlation with the risk factors of macrovascular complications. The intima- media thickness correlated with the incidence of macrovascular complications, and the relationship with diabetic nephropathy requires further study.

Methylenetetrahydrofolate Reductase Polymorphism in Korean Type 2 Diabetic Patients with Macroangiopathy.: Ki Won Oh, Won Young Lee, Yoo Bae Ahn, Ki Ho Song, Soon Jib Yoo, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 1999;23(5):625-634. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Hyperhomocysteinemia is an inde-pendent risk factor for cardiovascular disease. Recently, a mutation (677CT) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene, leading to the substitution of valine (V) for alanine (A). This mutation causes a reduced folate-dependent enzyme activity which leads to increased homocysteine. In this study, we examined the association between the V allele of the methylenetetrahydrofolate reductase gene and macroangiopathy in Korean patients with type 2 diabetes mellitus. METHODS: In 54 type 2 diabetic patients with macroangiopathy and 198 normal subjects, the MTHFR genotypes were analyzed by polymerase chain reaction (PCR), followed by Hinfl digestion. To confirm the detection of the MTHFR polymorphism by the PCR-restriction fragment length polymorphism (RFLP) analysis, DNA Sequencing was performed on the PCR products. RESULT: The allele frequency of the V mutation was slightly higher in the patients than in the normal subjects, but that was statistically not significant. The crude ORs and 95% CIs for the allele frequency of the V mutation were 1.16 (0.76~1.79). Genotype frequencies were 35.9% for AA, 48.4% for AV, and 15.7% for VV in the normal subjects. And they were 31.5% for AA, 50.0 % for AU, and 18.5 % for VV in the patients. The crude ORs and 95% CIs for the VV genotype were 1.22 (0.56~2.67). In multiple regressian model, the VV genotype was not associated with diabetic macroangiopathy. CONCLUSION: Although, the frequencies of VV genotype in Korean normals (=16%) are higher than those of other thical populations (=12%), this mutation is not associated with macroangiopathy in type 2 diabetic patients. But, our sample size was too small and larger cohort studies will be needed to confirm the effect of MTHFR polymorphism on the development of macroangiopathy in diabetic patients.

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