Vitamin D in Patients With T2DM on Different Regimens
Vitamin D in Patients With T2DM on Different Regimens
We have already demonstrated from previous cross-sectional observations that non-diabetic adults are more vitamin D deficient than DMT2 adults, probably because of improved diet and multi-vitamin supplementation. We have also shown that vitamin D supplementation even up to 18 months is not sufficient to fully correct vitamin D status, but nevertheless confers improvement in the metabolic profiles among the DMT2 adults, including insulin sensitivity. The significant improvements in the metabolic status of DMT2 subjects secondary to vitamin D supplementation have also been documented in other interventional and clinical trial studies with respect to glucose homeostasis, although beneficial effects in vascular function fell short. A recent review by Pilz and colleagues observed that the modest effects of vitamin D on glycemic control and insulin resistance in a few randomized controlled trials are insufficient to recommend vitamin D supplementation for DMT2 patients. The present interventional study highlighted how the different anti-diabetic therapies influence/interfere with circulating levels of 25-OHVitD before and after 12-months of vitamin D supplementation, and shed light as to how these anti-DM therapies inhibit/activate the beneficial effects of such intervention.
In the rosiglitazone group, vitamin D supplementation increased the mean circulating 25-OHVitD level of all subjects and had favorable effects on the circulating triglycerides, which was observed only in males. Current evidence states that rosiglitazone is not superior to other anti-diabetic drugs, such as metformin, when it comes to improving lipid profile. Nevertheless, rosiglitazone affects vitamin D status by selective agonism of peroxisome proliferator activated receptors (PPAR-gamma), which are present in muscle, liver and adipose tissue. It is probably through the agonist effect of rosiglitazone on circulating 25-OHVitD levels that indirectly contributed to the parallel improvement of triglycerides, at least in the male group since no information was available in females.
In the insulin alone group, significant improvement was observed in the mean total cholesterol of females, while other metabolic parameters remained unchanged. The finding is in accordance with a recent clinical trial done in females with polycystic ovary syndrome (PCOS), who also benefitted from vitamin D3 supplementation in terms of decreased cholesterol levels. However, the improvement in the cholesterol levels secondary to vitamin D correction were not observed in other trials involving the general population in both the short- and long term.
In contrast, the insulin + oral agents group showed more significant improvements in the metabolic profile, which included triglycerides and total cholesterol, as well as systolic blood pressure and HDL-cholesterol in the males. Vitamin D correction may protect against increased cardiovascular risk through the promotion of large HDL particle formation, which increases reverse cholesterol transport. These large HDL-cholesterol particles may form because of stimulation of apolipoprotein A1, the largest component of HDL-cholesterol, by vitamin D. While the mechanism of why this effect was only apparent in the insulin + oral agents group cannot be addressed in the present study, it is worthy to mention that vitamin D correction under this particular regimen was more beneficial in terms of improving cardiometabolic profile than the standard DMT2 treatments.
No significant changes were seen in other groups (metformin, oral agent-combinations and sulphonylurea) in relation to vitamin D supplementation, with the exception of increased levels of 25-OHVitD. Of note is the lack of a significant increase in the HDL-cholesterol levels of the sulphonylurea group, which can be clinically favorable, since DM patients on sulphonylureas had a lower HDL-cholesterol than DMT2 patients on insulin and diet, not to mention the lower ability of sulphonylureas to improve the lipid profile, making it a positive risk factor for ischemic heart disease in patients with DMT2. It is also clinically favorable in the sense that most probably the vitamin D supplementation is sufficient to counteract the HDL-lowering ability of sulphonylureas, but not sufficient in increasing HDL-levels, making the final level similar to previous measurements. Furthermore, the increased 25-OHVitD levels in the metformin group with no added metabolic improvements may imply, at least, that metformin does not affect negatively vitamin D correction in these patients.
The authors acknowledge several limitations. The small sample size of some DMT2 groups may have created bias and thus results from these groups should be interpreted with caution. Other confounders, such as diet and physical activity, were not accounted for in the study. Furthermore the mean doses of medications were not documented and therefore the dose dependent effect cannot be verified. Nevertheless, this is one of the first studies to compare how different DMT2 therapies affect vitamin D supplementation. While all groups seemed to increase their levels of 25-OHVitD after onset supplementation, it appears that those DMT2 patients on insulin in combination with other drugs was the group that benefitted the most as compared with other groups in terms of improving cardiovascular risk. Further studies on the effects of vitamin D supplementation in harder outcomes such as HOMA β-function in these groups should be considered.
Discussion
We have already demonstrated from previous cross-sectional observations that non-diabetic adults are more vitamin D deficient than DMT2 adults, probably because of improved diet and multi-vitamin supplementation. We have also shown that vitamin D supplementation even up to 18 months is not sufficient to fully correct vitamin D status, but nevertheless confers improvement in the metabolic profiles among the DMT2 adults, including insulin sensitivity. The significant improvements in the metabolic status of DMT2 subjects secondary to vitamin D supplementation have also been documented in other interventional and clinical trial studies with respect to glucose homeostasis, although beneficial effects in vascular function fell short. A recent review by Pilz and colleagues observed that the modest effects of vitamin D on glycemic control and insulin resistance in a few randomized controlled trials are insufficient to recommend vitamin D supplementation for DMT2 patients. The present interventional study highlighted how the different anti-diabetic therapies influence/interfere with circulating levels of 25-OHVitD before and after 12-months of vitamin D supplementation, and shed light as to how these anti-DM therapies inhibit/activate the beneficial effects of such intervention.
In the rosiglitazone group, vitamin D supplementation increased the mean circulating 25-OHVitD level of all subjects and had favorable effects on the circulating triglycerides, which was observed only in males. Current evidence states that rosiglitazone is not superior to other anti-diabetic drugs, such as metformin, when it comes to improving lipid profile. Nevertheless, rosiglitazone affects vitamin D status by selective agonism of peroxisome proliferator activated receptors (PPAR-gamma), which are present in muscle, liver and adipose tissue. It is probably through the agonist effect of rosiglitazone on circulating 25-OHVitD levels that indirectly contributed to the parallel improvement of triglycerides, at least in the male group since no information was available in females.
In the insulin alone group, significant improvement was observed in the mean total cholesterol of females, while other metabolic parameters remained unchanged. The finding is in accordance with a recent clinical trial done in females with polycystic ovary syndrome (PCOS), who also benefitted from vitamin D3 supplementation in terms of decreased cholesterol levels. However, the improvement in the cholesterol levels secondary to vitamin D correction were not observed in other trials involving the general population in both the short- and long term.
In contrast, the insulin + oral agents group showed more significant improvements in the metabolic profile, which included triglycerides and total cholesterol, as well as systolic blood pressure and HDL-cholesterol in the males. Vitamin D correction may protect against increased cardiovascular risk through the promotion of large HDL particle formation, which increases reverse cholesterol transport. These large HDL-cholesterol particles may form because of stimulation of apolipoprotein A1, the largest component of HDL-cholesterol, by vitamin D. While the mechanism of why this effect was only apparent in the insulin + oral agents group cannot be addressed in the present study, it is worthy to mention that vitamin D correction under this particular regimen was more beneficial in terms of improving cardiometabolic profile than the standard DMT2 treatments.
No significant changes were seen in other groups (metformin, oral agent-combinations and sulphonylurea) in relation to vitamin D supplementation, with the exception of increased levels of 25-OHVitD. Of note is the lack of a significant increase in the HDL-cholesterol levels of the sulphonylurea group, which can be clinically favorable, since DM patients on sulphonylureas had a lower HDL-cholesterol than DMT2 patients on insulin and diet, not to mention the lower ability of sulphonylureas to improve the lipid profile, making it a positive risk factor for ischemic heart disease in patients with DMT2. It is also clinically favorable in the sense that most probably the vitamin D supplementation is sufficient to counteract the HDL-lowering ability of sulphonylureas, but not sufficient in increasing HDL-levels, making the final level similar to previous measurements. Furthermore, the increased 25-OHVitD levels in the metformin group with no added metabolic improvements may imply, at least, that metformin does not affect negatively vitamin D correction in these patients.
The authors acknowledge several limitations. The small sample size of some DMT2 groups may have created bias and thus results from these groups should be interpreted with caution. Other confounders, such as diet and physical activity, were not accounted for in the study. Furthermore the mean doses of medications were not documented and therefore the dose dependent effect cannot be verified. Nevertheless, this is one of the first studies to compare how different DMT2 therapies affect vitamin D supplementation. While all groups seemed to increase their levels of 25-OHVitD after onset supplementation, it appears that those DMT2 patients on insulin in combination with other drugs was the group that benefitted the most as compared with other groups in terms of improving cardiovascular risk. Further studies on the effects of vitamin D supplementation in harder outcomes such as HOMA β-function in these groups should be considered.
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