Some antipsychotics, such as quetiapine and olanzapine, are associated with the occurrence of high blood sugar and an increased risk of type II diabetes. These drugs are used to treat a wide variety of mental disorders, including schizophrenia, bipolar disorder, depression and sleep disorders. However, the side effects limit their clinical use.
Despite the widely known relationship between these types of antipsychotics and type II diabetes, the pathogenesis of drug induced type II diabetes remains poorly understood. Scientists have proposed several mechanisms for anti-psychotic induced diabetes, including weight gain, decreased insulin secretion from the pancreas, insulin resistance and impaired leptin production. Researchers recently conducted a search for drug combinations in the FDA Adverse Event Reporting (FAERS) database to identify drugs or supplements that would reduce the risk of antipsychotic induced diabetes.
Here is what the researchers found regarding the antipsychotics and the risk of type II diabetes:
- Those who took quetiapine and olanzapine experienced type II diabetes related adverse events twenty times more often than those who did not take the drugs.
- After adjusting for various potential confounding factors, such as age, gender, mental illness and combinatorial drug therapy, the relationship between quetiapine and type II diabetes related adverse events remained the same. This indicated that quetiapine use is associated with an increased occurrence of type II diabetes regardless of age, gender, mental illness or combinatorial drug therapy.
- The lowest risk for quetiapine induced diabetes was observed when an individual was taking vitamin D. This effect was also seen in combinatorial therapy with olanzapine.
- Those who took vitamin D experienced quetiapine induced type II diabetes events significantly less frequently than those who did not supplement with vitamin D. However, vitamin D by itself did not reduce the frequency of diabetes related adverse events for those who were not on antipsychotics.
To verify the observed association between vitamin D supplementation and reduced risk of quetiapine-induced hyperglycemia, the researchers conducted an animal study. Male mice were fed a control or vitamin D supplemented diet for one week. A glucose tolerance test was administered to the mice to measure baseline glucose levels. Then, the mice were given quetiapine. Quetiapine led to significantly higher blood glucose levels in the mice given the control diet (p < 0.001). The vitamin D supplementation significantly reduced the risk of quetiapine induced increases in both glucose and insulin (p < 0.05).
Next, the researchers investigated the effects of both vitamin D and quetiapine use on the expression of 24 genes involved in the insulin resistance pathway. They found that the expression of ten insulin resistance-related genes were downregulated in rat liver after oral quetiapine administration, while only one gene was upregulated. The most prominent reduction in expression was observed for the gene Pik3r1, which encodes a protein that plays a vital role in the metabolic actions of insulin. Furthermore, a mutation in the Pik3r1 gene is linked with insulin resistance. Thus, the researchers hypothesized that vitamin D decreases quetiapine-induced hyperglycemia by inhibiting the downregulation of Pik3r1.
To test this hypothesis, the researchers examined the ability of vitamin D supplementation to block the antipsychotic induced changes in gene expression. After administration of the glucose tolerance test in mice, the researchers measured the gene levels. A decreased expression of Pik3r1 was observed within two hours after treatment with quetiapine; although this did not quite reach statistical significance (p = 0.079). The decreased expression of Pik3r1 was significantly reversed by vitamin D supplementation (p < 0.05). Significant increased levels of Insr, the gene that encodes the insulin receptor, was also observed in the vitamin D group (p < 0.01).
The researchers concluded,
“The current data mining predictive analysis with experimental validation provides the first indication that vitamin D can prevent antipsychotic-induced hyperglycemia by suppressing insulin resistance via upregulation of Pik3r1.”
The study consisted of several limitations to note. First, the study used data mining to identify vitamin D as a potential mediator for the risk of antipsychotic induced diabetes. While data mining can serve as a useful and effective tool for research, it can also incorporate bias into a study. The FAERS database consists of voluntary reports for adverse events and medication errors by both healthcare professionals and consumers; therefore recall bias and selection bias may skew results. Lastly, the researchers tested their hypothesis using an animal study. The effects seen in an animal experiment may not always be replicated in humans.
Tovey, A. Research suggests vitamin D may reduce risk of diabetes while on antipsychotic drugs. The Vitamin D Council Blog & Newsletter, 2016.
Nagashima T. et al. Prevention of antipsychotic-induced hyperglycaemia by vitamin D: a data mining prediction followed by experimental exploration of the molecular mechanism. Scientific Reports, 2016.