Effect of vitamin B12 supplementation on glycemic control in poorly controlled hyperhomocysteinemic type 2 diabetic patients
Abstract
This study was conducted to observe the effect of vitamin B12 supplementation on glycemic control in poorly controlled hyperhomocysteinemic type 2 diabetic patients by measuring HbA1c levels at baseline and 4 weeks. Patient having serum homocysteine more than 15 µmol/L or vitamin B12 less than 223 pg/mL were enrolled in this study. One group received methylcobalamin 500 µg daily with their usual antidiabetic therapy and the other group received only suitable antidiabetic drug therapy. Methylcobalamin 500 µg was given daily for period of 4 weeks. Glycemic control was measured by levels of HbA1c, blood sugar at baseline and at 4 weeks. Serum homocysteine levels was reduced from 21.5 ± 2.6 to 15.4 ± 6.4 (p=0.04) with vitamin B12 supplementation at 4 weeks. At 4 weeks, HbA1c decreased from 9.9 ± 0.9 to 8.7 ± 0.5 (p<0.01) in vitamin B12 deficient patients after vitamin B12 supplementation. There is role of vitamin B12 in glycemic control in poorly controlled type 2 diabetic patients.
Introduction
Hyperhomocysteinemia is observed in type 2 diabetes and it is associated with macroangiopathy, nephropathy and microalbuminuria (Buysschaert et al., 2000; Jager et al., 2001). Hyperhomocysteinemia is a risk factor for atherosclerosis (Mahendran et al., 2013). Moderately raised plasma homocysteine was obtained with associated decreased folic acid and vitamin B12 levels in type 2 diabetes subjects (Soinio 2004; Klee 2000; Ebesunun and Obajobi, 2012). Raised homoysteine levels are associated with raised levels of bad cholesterol and decreased levels of good cholesterol (Mahendran et al., 2013; Ramachandran et al., 2012).
Homocysteine is independently associated with the prevalence of diabetic neuropathy in type 2 diabetic patients (Ambrosch 2001). Metformin also causes vitamin B12 deficiency. There is no evidence that pathological levels of the biochemical markers of B12 are more common in metformin-treated compared with non–metformin-treated patients, despite lowering B12 in serum or plasma (Obeid, 2014).
Vitamin B12 100 µg alternate day with low fat vegan diet resulted in improvement in glycemic and lipid control (Barnard et al., 2006) Therapy with folic acid, vitamin B12, and vitamin B6 significantly decreases the incidence of major adverse events after percutaneous coronary intervention (Schnyder 2002). This study was planned to study effect of vitamin B12 supplementation on glycemic control in poorly controlled hyperhomocysteinemic type 2 diabetic patients with objectives: a) glycemic control measured by levels of glycosylated hemoglobin (HbA1c) at baseline and 4 weeks; b) fasting blood sugar level at baseline and 4 weeks; c) serum homocysteine/vitamin B12 levels at baseline and 4 weeks; d) serum lipid profile at baseline and 4 weeks.
Materials and Methods
Patients not responding adequately to oral antidiabetic agents were recruited from Medicine OPD with the help of treating physician. Patient were first screened for serum homocysteine/vitamin B12 level along with all baseline investigations. Those having serum homocysteine level more than 15 µmol/L or vitamin B12 level less than 223 pg/mL were enrolled in this study. Due to high cost for investigation, serum homocysteine level was measured only in 6 patients and serum vitamin B12 level was measured in 14 patients with prior permission from Ethics Committee.
Inclusion criteria for this study were: Age between 30 -70 years, male, non-lactating female, HbA1 >8%, serum homocysteine >15 µmol/L or serum vitamin B12 level <223 pg/mL ischemic heart disease (IHD) or non-IHD patients. Exclusion criteria were: Age <30 years, pregnancy, lactating mother, patient with insulin dependent diabetes mellitus, severe and complicated diabetes, patients with hepatic or renal dysfunction. After enrolment of patients for the study, all the baseline investigations were carried out at Central Clinical Laboratory except Hb1Ac which was carried out at Department of Pharmacology. Serum homocysteine or vitamin B12 estimation was carried out in an accredited laboratory. There were two groups of poorly controlled patient; Drug group received methylcobalamin 500 µg daily with their usual antidiabetic therapy and the control group received suitable antidiabetic drug therapy as prescribed by treating physician. Methylcobalamin 500 µg was given once daily for the period of 4 weeks and were followed-up at 4 weeks. At baseline all the investigations were carried out (Figure 1).
Figure 1: Flow chart of investigations
Reporting of adverse effects
All patients were given checklist of adverse effects of vitamin B12 and information about adverse drug reactions was collected in follow-up. Patients unable tolerate adverse drug reactions, were advised to contact any of investigators at any time for review and advice.
Sample size calculation and statistical analysis
Sample size of 20 for each group was calculated in the ratio of 1, power 80%, considering 10-fold difference of drug effect in vitamin B12 group and control group by using Open Epi 2.3 (2009). Randomization was done with the help of randomization software (Rando 1.2, 2004). Statistical analysis was done by using Open Epi 2.3, 2009) and Microsoft Excel.
Results
In this study, 20 patients completed study in drug group and 18 patients in control group. There was no significant difference in demography in both the groups. There was no significant difference in baseline parameters (Table I)
Table I: Demographic characteristics
| Parameter | Drug group (n=20) | Control group (n=18) |
|---|---|---|
| Sex | ||
| Male | 3 (15%) | 4 (22.2%) |
| Female | 17 (85%) | 14 (77.7%) |
| Age (years) | 51.8 ± 8.9 | 55.1 ± 7.9 |
| Weight (kg) | 61.0 ± 5.9 | 60.8 ± 11.9 |
| HbA1c (%) | 10.0 ± 0.8 | 9.3 ± 1.0 |
| Fasting blood sugar level (mg/dL) | 157.6 ± 61.3 | 132.1 ± 29.7 |
| Postprandial blood sugar level (mg/dL) | 239.2 ± 111.2 | 208.7 ± 62.3 |
| Data are mean ± SD | ||
There was significant fall in serum homocysteine levels with vitamin B12 supplementation in hyperhomocystenemic type 2 diabetic patients at 4 weeks. No significant fall in blood sugar levels and HbA1c levels was observed after vitamin B12 supplementation in hyper-homocystenemic type 2 diabetic patients at 4 weeks. No significant beneficial effect was observed on lipid profile at 4 weeks after vitamin B12 supplementation(Table II).
Table II: Vitamin B12 supplementation on glycemic control and lipid profile in hyperhomocystenemic poorly controlled type 2 diabetic patients
| Parameter | Baseline | After 4 weeks | p value |
|---|---|---|---|
| Serum homocysteine (µmol/L) | 21.5 ± 2.6 | 15.4 ± 6.4 | 0.04 |
| HbA1c (%) | 10.0 ± 0.6 | 9.8 ± 0.8 | 0.57 |
| Fasting blood sugar level (mg/dL) | 181.5 ± 99.8 | 152.5 ± 65.1 | 0.57 |
| Postprandial blood sugar level (mg/dL) | 300.3 ± 193.8 | 260.6 ± 146.7 | 0.69 |
| HDL (mg/dL) | 41.9 ± 12.5 | 44.2 ± 12.1 | 0.75 |
| Total cholesterol (mg/dL) | 159.3 ± 25.4 | 156.8 ± 36.5 | 0.89 |
| Triglycerides (mg/dL) | 108.1 ± 32.5 | 105.9 ± 41.6 | 0.92 |
| Data are mean ± SD | |||
There was significant rise in vitamin B12 levels and significant fall in HbA1c levels in vitamin B12 deficient patients with vitamin B12 supplementation at 4 weeks (Table III).
Table III: Vitamin B12 supplementation on glycemic control in vitamin B12 deficient poorly controlled type 2 diabetis
| Parameter | Baseline | After 4 weeks | p value |
|---|---|---|---|
| Serum vitamin B12 (pg/mL) | 203.8 ± 17.6 | 515.1 ± 77.4 | <0.01 |
| HbA1c (%) | 9.9 ± 0.9 | 8.7 ± 0.5 | <0.01 |
| Fasting blood sugar level (mg/dL) | 147.3 ± 35.9 | 130.3 ± 32.6 | 0.21 |
| Postprandial blood sugar level (mg/dL) | 213.0 ± 34.4 | 196.2 ± 59.7 | 0.37 |
| Data are mean ± SD | |||
Combined data of poorly controlled hyperhomocystenemic and vitamin B12 deficient type 2 diabetic patients had shown significant fall in HbA1c levels at 4 weeks (Table IV).
Table IV: Effect of vitamin B12 supplementation on glycemic control in poorly controlled type 2 diabetic patients
| HbA1c (%) | Fasting blood sugar level (mg/dL) | Postprandial blood sugar level (mg/dL) | ||||
|---|---|---|---|---|---|---|
| Baseline | 4 weeks | Baseline | 4 weeks | Baseline | 4 weeks | |
| Drug group (n=20) | 10.0 ± 0.8 | 9.0 ± 0.8a | 157.6 ± 61.3 | 137.3 ± 44.7 | 239.2 ± 111.2 | 216.5 ± 96.4 |
| Control group(n=18) | 9.3 ± 1.0 | 9.2 ± 0.8 | 132.1 ± 29.7 | 140.6 ± 42.3 | 208.7 ± 62.3 | 222.1 ± 61.2 |
| P value (compared with control) | 0.02 | 0.43 | 0.11 | 0.81 | 0.29 | 0.83 |
| ap<0.001 (paired t test as compared to baseline values) | ||||||
Discussion
In this study, a dose 500 μg/day was used orally for 4 weeks in poorly controlled type 2 diabetic patients with either hyperhomocysteinemia or vitamin B12 deficiency. There was significant decrease in levels of homocysteine from 21.5 ± 2.6 to 15.4 ± 6.4, (p=0.04) with vitamin B12 supplementation for four weeks. In vitamin B12 deficient and hyperhomocystenemic type 2 diabetic patients, there was significant decrease in HbA1c levels from 9.9 ± 0.9 to 8.7 ± 0.5, (p<0.01) with vitamin B12 supplementation for 4 weeks. This study has proved that vitamin B12 alone can also reduce homocysteine level in hyperhomocystenemic type 2 diabetic patients.
In adult patients with type 2 diabetes, intra muscular or oral vitamin B12 in doses of 1000 μg daily for a week then once every week for 4 weeks are sufficient to correct vitamin B12 deficiency (Kibirige and Mwebaze, 2013). Vitamin B12 100 μg alternate day with low fat vegan diet resulted in improvement in glycemic and lipid control (Barnard et al., 2006). Therapy with folic acid, vitamin B12, and vitamin B6 significantly decreases the incidence of major adverse events after percutaneous coronary intervention (Schnyder et al., 2002). Vitamin B12 replacement has been shown to cause symptomatic improvement among patients with severe diabetic neuropathy (Kibirige and Mwebaze, 2013; Talaei et al., 2009).
As higher homocysteine level in poorly controlled type 2 diabetic patient is associated with poor glycemic control (raised HbA1c) and micro-macro vascular complication (Ramachandran et al., 2012), correction of homocysteine level and correction of vitamin B12 deficiency which is one of the factor raised homocysteine level would have resulted in beneficial improvement in HbA1c in this study. For confirmation of the role of vitamin B12 in glycemic control vitamin B12 deficient patients further studies are needed in poorly controlled type 2 diabetic patients.
Conclusion
Homocysteine level reduced significantly after vitamin B12 supplementation for 4 weeks in hyperhomocysteinemic poorly controlled type 2 diabetic patients. In vitamin B12 deficient, there was significant fall in HbA1c levels after vitamin B12 supplementation for 4 weeks. There is role of vitamin B12 in glycaemic control in type 2 diabetic patients.
Ethical Issue
The study protocol was approved by the local Institutional Ethics Committee. Patients were given all the information about vitamin B12 (methylcobalamin) including adverse effects. A written informed consent was taken from each patient and those who were willing to participate in study were enrolled in this study. All the information was recorded in case report forms. The study was registered in clinicaltrials.gov (NCT02540642).
References
Ambrosch A. Relation between homocysteinaemia and diabetic neuropathy in patients with type 2 diabetes mellitus. Diabetic Med. 2001; 18: 185-92.
Buysschaert M, Dramais A-S, Wallemacq PE, Hermans MP: Hyperhomocysteinemia in type 2 diabetes: Relationship to macroangiopathy, nephropathy, and insulin resistance. Diabetes Care. 2000; 23: 1816–22.
Barnard ND, Cohen J, Jenkins DJ, Turner-Mc Grievy G, Gloede L, Jaster B, Seidl K, Green AA, Talpers S. A low fat vegan diet improves glycaemic control and cardiovascular risk factors in randomized clinical trial in individuals with type 2 diabetes. Diabetes Care. 2006; 29: 1777-83.
Ebesunun MO, Obajobi EO. Elevated plasma homocysteine in type 2 diabetes mellitus: A risk factor for cardiovascular diseases. Pan African Med J. 2012; 12: 48.
Jager A, Kostense PJ, Nijpels G, Dekker JM, Heine RJ, Bouter LM, Donker AJM, Stehouwer CD. Serum homocysteine levels are associated with the development of (micro)albuminuria: The Hoorn Study. Arterioscler Thromb Vasc Biol. 2001; 21: 74-81.
Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with diabetes mellitus: Is routine screening and supplementation justified? J Diabetes Metabol Dis. 2013; 12: 17.
Klee GG. Cobalamin and folate evaluation: Measurement of methylmalonic acid and homocysteine vs vitamin B12 and folate. Clin Chem. 2000; 46: 1277-83.
Mahendran KB, Santha K, Santhoshkumar N, Desigan EG, Mohammad A. Serum homocysteine and lipid profile levels in type 2 diabetes mellitus patients. Int J Med Res Health Sci. 2013; 2: 200-05.
Obeid R. Metformin causing vitamin B12 deficiency: A guilty verdict without sufficient evidence. Diabetes Care. 2014; 37: e22–23.
Ramachandran L, Negi NS, Gupta B. Prevalence of hyperhomocysteinaemia in type 2 diabetes mellitus and its correlation with its complications. J Ind Aca Clin Med. 2012; 13: 277-81.
Schnyder G. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after Percutaneous Coronary Intervention The Swiss Heart Study: A randomized controlled trial. JAMA. 2002; 288: 973-79.
Soinio M. High Homocysteine levels increase risk for heart attacks in people with type 2 diabetes mellitus. Ann Intern Med. 2004; 140: 1-31.
Talaei A, Siavash M, Majidi H, Chehrei A. Vitamin B12 may be more effective than nortriptyline in improving painful diabetic neuropathy. Int J Food Sci Nutr. 2009; 60: 71–76.
