Correlation between vitamin B12 deficiency and hemoglobin A1c in patients with diabetes mellitus

1. Introduction

Diabetes mellitus is characterized by persistent hyperglycemia (Aroda et al., 2016). Current research indicates a strong correlation between the development of diabetes and glycemic management based on measurement of the circulating levels of glycosylated hemoglobin A1c (HbA1c) (de Boer et al., 2011). Since elevated HbA1c levels are associated with micro- and macrovascular illness, it is critical to identify modifiable aspects of glucose metabolism. Recent studies have focused on vitamin B12 insufficiency because of its possible link to glycemic dysregulation (De Groot et al., 2013). Recent studies indicate that vitamin B12 deficiency may disrupt glucose homeostasis and, especially in patients with type 2 diabetes undergoing metformin treatment (De Groot et al., 2013). This may indicate a correlation between vitamin B12 deficiency and HbA1c levels. To build on this, it is essential to understand the physiological importance of vitamin B12.

The production of RBCs, DNA synthesis, and nervous system function all depend on vitamin B12, a water-soluble vitamin (He et al., 2022). Vitamin B12 deficiency is very common and affects a significant percentage of people with type 2 diabetes mellitus (T2DM) and older adults (Liu et al., 2022). Vitamin deficiency is known to cause numerous conditions, including megaloblastic anemia and neuropathy (established side effects of diabetes) (Malla et al., 2022; Obeid et al., 2013). Fatigue, weakness, migraines, and nerve damage are all signs of a B12 deficiency. Even though the human liver can store B12 for many years, poor diet or illnesses like diabetes can lead to its deficiency (Swidan and Ahmed, 2016). B12 plays a crucial role in two key biochemical processes: homocysteine to methionine conversion (important for healthy cell function) and promoting cellular energy metabolism (Jatoi et al., 2020). Vitamin B12 deficiency can lead to toxin accumulation, nerve myelin sheath damage, and nerve-related conditions ranging from sensory changes and memory loss to more severe conditions, such as spinal cord disease and Alzheimer's disease (AD) (Swidan and Ahmed, 2016; Jatoi et al., 2020; Infante et al., 2021). Given its systemic role, identifying contributing factors to B12 deficiency becomes critical in diabetic patients.

Metformin (used for T2D treatment) can cause vitamin B12 malabsorption and may lead to its deficiency in patients with diabetes (He et al., 2022; Niafar et al., 2014). A recent meta-analysis has shown that patients with T2D receiving metformin had significantly reduced vitamin B12 levels, likely because metformin may impair long-term gastrointestinal B12 absorption; this may result from various factors, including a decrease in calcium-dependent absorption, slowed digestion, bacterial overgrowth, or changes in bile acid metabolism. However, studies have shown that this effect can be mitigated by taking calcium supplements, which help restore normal B12 absorption. Vitamin B12 deficiency is typically diagnosed through blood tests, although the specific diagnostic thresholds may vary slightly between different medical organizations (Swidan and Ahmed, 2016; Jatoi et al., 2020; Infante et al., 2021; Niafar et al., 2014). Such findings support the need to evaluate how vitamin B12 status may intersect with diabetic treatment regimens and patient outcomes.

Mathai et al. studied the correlation between vitamin B12 levels and metformin use in patients with T2DM, comparing changes in vitamin B12 levels with glycemic control, metformin dose, and treatment duration (Ko et al., 2014). The blood glucose profiles of participants were assessed using fasting glucose concentration (FGC) and postprandial blood glucose levels (PPBG). The results showed that individuals in Category 3 (those with poor blood sugar control) had significantly higher FGC, PPBG, and HbA1c levels compared to those in Category 2 (good control) and Category 1 (healthy individuals). Additionally, an inverse relationship was found between vitamin B12 status and both the dose of metformin and the duration of its use in participants from Categories 2 and 3. The study concluded that patients who took higher doses of metformin or had been using the drug for a longer period were more likely to have lower vitamin B12 levels (Ko et al., 2014). This raises the question of whether vitamin B12 status might directly influence glycemic biomarkers such as HbA1c.

Current literature presents conflicting data on the correlation between vitamin B12 and HbA1c. Several studies implicate vitamin B12 deficiency with glycemic dysregulation, while others argue that this correlation may reflect inaccurate measurements, particularly in patients with reduced erythrocyte turnover (Kibirige and Mwebaze, 2014). Sex and age may also impact vitamin B12 levels and their relationship with HbA1c (see Table 1), although these relationships are not well understood (Umay et al., 2011). Considering these discrepancies, a focused investigation is needed to clarify this relationship across different demographic groups.

We aimed to assess the relationship between vitamin B12 levels and HbA1c in patients with diabetes and identify differences across age and sex (Owen et al., 2021). We employed statistical methods to identify factors associated with vitamin B12 deficiency and diabetes control, and evaluated whether targeted interventions may improve diabetes management.

2. Materials and Methods

3. Results

Data from 364 patients with diabetes, including 202 women and 162 men, were used to assess the relationship between vitamin B12 deficiency and HbA1c levels, with additional comparisons to age and sex.

3.1 Descriptive statistics

Table 3 presents descriptive statistics for two cohorts based on sex and age, focusing on two key measures: HbA1c and vitamin B12 levels. These Tables show the minimum, maximum, mean, and SD values of HbA1c and vitamin B12 levels for each subgroup. Overall, the mean vitamin B12 value was 460.34 pg/mL (SD = 256.36, range, 36.90-1476.0 pg/mL). The mean HbA1c value for the overall population was 8.55% (SD = 1.77; range, 6.7% –16.8%). When comparing age groups, individuals ≥60 years exhibited a higher mean vitamin B12 value (556.31 pg/mL, SD = 303.43) than those <60 years (430.65 pg/mL, SD = 232.66). The mean HbA1c values were slightly higher in the ≥60 (8.76%, SD = 1.67) compared with the <60 years group (8.48%, SD = 1.80). Examining gender differences, men had a higher mean vitamin B12 value (489.10 pg/mL, SD = 254.72) than women (437.27 pg/mL, SD = 255.97). The mean HbA1c level for men was higher (8.67%, SD = 1.85) compared with women (8.46%, SD = 1.70). Within specific subgroups, men <60 years of age displayed a mean vitamin B12 value of 451.37 pg/mL, while women <60 years had a mean value of 416.24 pg/mL. For those ≥60, men displayed a mean B12 value of 578.71 pg/mL, and women exhibited a mean B12 value of 528.01 pg/mL. Interestingly, HbA1c levels were higher for women ≥60 (9.07%, SD = 1.90) compared with men ≥60 years (8.52%, SD = 1.44).

Table 3. Descriptive statistics for patient cohort.

Group	Vitamin B12 (pg/mL) mean	Vitamin B12 (pg/mL) min	Vitamin B12 (pg/mL) max	Vitamin B12 (pg/mL) SD	HbA1c (%) mean	HbA1c (%) min	HbA1c (%) max	HbA1c (%) SD
Overall	460.34	36.9	1476	256.36	8.55	6.7	16.8	1.77
< 60	430.65	36.9	1476	232.66	8.48	6.7	16.8	1.8
> 60	556.31	79.14	1476	303.43	8.76	6.7	14.4	1.67
Men	489.1	93.14	1476	254.72	8.67	6.7	16.8	1.85
Women	437.27	36.9	1476	255.97	8.46	6.7	14.5	1.7
< 60, Men	451.37	93.14	1476	220.55	8.73	6.7	16.8	2
< 60, Women	416.24	36.9	1476	240.32	8.31	6.7	14.5	1.62
> 60, Men	578.71	118.1	1476	306.02	8.52	6.7	12.9	1.44
> 60, Women	528.01	79.14	1476	301.81	9.07	6.7	14.4	1.9

The analysis showed that HbA1c levels tended to increase with age, with older individuals (60+) having higher mean HbA1c values compared to younger ones. For women, the mean HbA1c increased from 8.31% to 9.07%, and for men, it shifted from 8.73% to 8.52%. In contrast, vitamin B12 levels were higher in older adults, with mean values rising from 416.24 pg/mL in women <60 to 528.01 pg/mL in those ≥60, and from 451.37 pg/mL in men <60 to 578.71 pg/mL in those ≥60. The data also showed increased variability in both HbA1c and vitamin B12 levels with age, suggesting that both HbA1c and vitamin B12 levels rise in older adults, with greater variability observed across the groups (Fig. 1).

Close

Fig. 1.

Vitamin B12 levels in study participants. This data illustrates the distribution of Vitamin B12 levels across different age categories for both women and men, categorizing individuals with levels either below or above 200 pg/mL.

Export to PPT

3.3 Statistical comparison of HbA1c levels between vitamin B12 deficient and non-deficient groups

We conducted Welch's two-sample t-test to evaluate the impact of vitamin B12 deficiency on HbA1c levels by comparing the mean HbA1c values between patients with and without vitamin B12 deficiency. Table 5 shows that individuals with vitamin B12 deficiency had a lower mean HbA1c value (07%, n = 45) compared with those who were non-deficient (8.62%, n = 319; 95% CI: -1.04, -0.05). Statistical testing using Welch's t-test resulted in a t-statistic of -2.156 and a p-value of 0.035, indicating a statistically significant difference between the two groups. This discrepancy is consistent with the slightly lower mean HbA1c levels that have been observed in women.

Table 5. T-test results comparing mean values of circulating levels of HbA1c and Vitamin B12.

Vitamin B12 group	Mean HbA1c levels	Count	t-Statistic	p-value:	95% Confidence interval for difference
Deficient	8.07	45	-2.156	0.035	(-1.04, -0.05)
Non-Deficient	8.62	319

To better illustrate the distribution of mean values in our population sample, we created a scatter plot (Fig. 2).

Close

Fig. 2.

Scatterplot of HbA1c versus vitamin B12 levels.

Export to PPT

3.4 Vitamin B12 deficiency proportional analysis

Table 6 provides an analysis of the vitamin B12 deficiency status in the <60 years and ≥60 years age groups. The threshold for vitamin B12 deficiency is commonly considered to be <200 pg/mL, although some guidelines may recommend slightly different values. Table 6 also presents the count and proportion of individuals in our patient cohort who were deficient and non-deficient in vitamin B12. Among those aged 60 and below, 36 individuals (12.67%) were B12 deficient, while 248 individuals (87.32%) were B12 non-deficient. In the ≥60 age group, nine individuals (11.25%) were B12 deficient, and 71 individuals (88.75%) were B12 non-deficient. Our data indicates that the B12 deficiency proportion was slightly higher in the <60 compared with the ≥60 age group. However, in both age categories, the vast majority of individuals were B12 non-deficient. A chi-square test examining the distribution of vitamin B12 deficiency between the two age groups yielded a p-value of 0.682, indicating that there was no significant difference in B12 deficiency rates between the groups.

Table 6. Age proportional analysis.

Age group	Deficient count	Non-deficient count	Deficient proportion	Non-deficient proportion
60 and below	36	248	0.1267	0.8732
Above 60	9	71	0.1125	0.8875

In the given data, individuals aged 60 and below had a higher prevalence of deficiency (36 cases) compared to those above 60 years (nine cases). However, no deficiency was more common in the younger group (248 cases) than in the older group (71 cases) (Fig. 3).

Our data revealed a higher prevalence of B12 deficiency in the <60 years age group (36 cases) compared with the ≥60 years age group (nine cases). However, vitamin B12 non-deficiency was also more common in the <60 years age group (248 cases) compared with the ≥60 years age group (71 cases) (Fig. 3).

Close

Fig. 3.

Comparison of deficiency rates between younger and older age groups.

Export to PPT

4. Discussion

This study elucidates the association between vitamin B12 insufficiency and glycemic regulation, with a specific focus on age- and sex-based stratification. By utilizing real-world clinical data, the analysis enhances current understanding of the demographic determinants that may modulate this metabolic relationship. Statistical analyses showed nuanced results. Pearson’s correlation analysis showed a correlation between vitamin B12 and HbA1c levels across different subgroups based on the overall population, age, and sex. The overall population showed a weakly positive association (r = 0.217) where elevated vitamin B12 levels correlated with increased HbA1c levels (CI, 0.12 to 0.31; p-value <0.001). For patients aged ≤ 60, vitamin B12 and HbA1c showed a weakly positive correlation (r = 0.185). Our present data align with previous reports showing that hyperglycemia leads to vitamin B12 becoming trapped in the bloodstream, leading to elevated vitamin B12 and HbA1c levels (Akabwai et al., 2015; Looker et al., 2007; Obeid et al., 2011; Li et al., 2022).

The results of Welch's two-sample t-test (Table 5) indicate that vitamin B12 deficiency may be associated with lower HbA1c levels (vitamin B12 deficient versus non-deficient group: HbA1c = 8.07 versus 8.62; t-test = -2.156, 95% CI, -1.04 to -0.05, respectively; p = 0.035). Likewise, data from Table 3 show that vitamin B12 levels increase with age (≥60 versus <60 age group: vitamin B12 levels = 556.31 pg/mL versus 430.65 pg/mL), possibly due to dietary factors, supplementation, or physiological changes with age. HbA1c levels show a modest increase with age (≥60 versus <60 age group: HbA1c levels = 8.76% versus 8.48%, respectively). Our data aligns with previous reports showing that HbA1c levels increase with age. The age-related elevation in HbA1c may be ascribed to diminished insulin sensitivity, compromised beta-cell functionality, and modified erythrocyte turnover, even in the absence of worsening glycemia (Dubowitz et al., 2014; Forbes et al., 2018; Oikonomidis et al., 2021; Langan et al., 2011).

Sex, age, and vitamin B12 deficiency comparisons revealed no significant difference in mean HbA1c values between women and men (8.46% vs. 8.67%, respectively), reflecting a predisposition among women to seek medical advice more readily and adhere to prescribed treatment regimens for diabetes. This feminine predisposition may also explain the slightly higher vitamin B12 levels in women, indicating a greater propensity for vitamin B12 supplementation.

Vitamin B12 deficiency prevalence differed with age (<60 age group: 36/284, 12.7% versus ≥60 age group: 9/80, 11.25%) but was not statistically significant, indicating possible age-related variations in vitamin B12 absorption, although dietary habits, comorbidities, and medication use (especially metformin) may also contribute (Oikonomidis et al., 2021). These data align with previous studies showing an association between vitamin B12 status and diabetes management, which suggests that low vitamin B12 levels may contribute to glycemic dysregulation and increased insulin resistance, although mechanisms remain unclear (Dubowitz et al., 2014). Our findings reinforce the hypothesis that vitamin B12 deficiency is prevalent among diabetics, especially those undergoing prolonged medication regimens that adversely impact nutrient absorption.

Although our findings provide valuable insights, they must be interpreted with caution due to several limitations. The cross-sectional study design restricts our ability to establish causal inferences regarding vitamin B12 deficiency and HbA1c levels. Future longitudinal studies involving larger, more diverse populations are warranted to determine directionality for this relationship. Further, other factors may influence vitamin B12 and HbA1c levels, including dietary habits, medication history, and genetic predisposition.

5. Conclusion

This study reveals a statistically significant positive correlation between vitamin B12 and HbA1c levels in diabetics, with B12-deficient individuals demonstrating lower HbA1c levels than those with sufficient B12 levels. Higher vitamin B12 levels in older adults may be attributed to physiological changes, dietary habits, or supplementation. No significant differences in vitamin B12 deficiency were found across age or sex groups. The results align with existing literature, indicating a potential impact of B12 deficiency on glycemic control, possibly due to impaired glucose metabolism. Although the cross-sectional nature of the study limits causal inferences, these findings highlight the importance of vitamin B12 monitoring in diabetics, especially those undergoing prolonged metformin treatment. Further, longitudinal studies are warranted to explore the directional relationship between B12 status and glycemic control in diabetes management.