Circadian Rhythm and Blood Sugar Control

The human body is an amazing machine. The biological clock that ticks inside us to keep the machine running efficiently not only prompts us to sleep and eat on regular basis, but also apparently regulates blood sugar.

Dr. Brian Feldman at Stanford University School of Medicine recently published a study suggesting that a class of steroid hormones called glucocorticoids have a direct effect on a number of genes that affect our biological clock, or circadian rhythm. The circadian rhythm, from the Latin words circa (around) and diem (day), is a 24-hour cycle of biochemical, physiological, and behavioral processes. Glucocorticoids are secreted from the adrenal gland, sometimes at high levels and sometimes at very low levels, depending upon the time of day, when we eat, and the types of food we consume. When blood sugar is lowest, glucocorticoid levels are highest, initiating gluconeogenesis to break down fat in the liver and thereby provide additional glucose to the blood.  

Glucocorticoids affect the immune system by up-regulating anti-inflammatory proteins and down-regulating pro-inflammatory proteins. In fact, glucocorticoids are marketed as nasal sprays, which alleviate inflamed nasal membranes, and as asthma inhalers, which reduce inflammation in the lungs. Prednisone, for example, is a prescribed corticosteroid (glucocorticoid) for the treatment of severe asthma or severe allergies. Although it is a valuable treatment option for some conditions, people with diabetes should be especially wary of taking such a powerful steroid because of the fact that glucocorticoids also stimulate gluconeogenesis. The consequent increase in available glucose would be a very serious side-effect for someone whose blood sugar levels are not well-controlled.

While it was thought that glucocorticoids triggered or synchronized the up-regulation and down-regulation of some circadian clock-associated genes, the how’s and why’s had not yet been well described.  Therefore, the first phase of Dr. Feldman’s study consisted of applying synthetic glucocorticoids to human and mouse stem cells grown in a dish, to see which genes in the stem cells were activated by the glucocorticoids. The researchers found that glucocorticoids directly activated several of the genes that control the circadian clock. 

The next step was to look at how the hormone’s control of the circadian clock was associated with other biological processes. Using mice that were genetically engineered to be missing a gene involved in circadian rhythm (Per2; one of the activated circadian clock genes), scientists were able to determine that while glucocorticoids had an effect on glucose homeostasis in normal control mice, there was no effect in mice missing the Per2 gene. This finding suggests that glucocorticoid regulation of circadian rhythm (by way of activating the Per2 gene) is directly involved in glucose homeostasis. Mice lacking the biological clock gene Per2 did not respond normally to glucose homeostasis challenges. These genetically engineered mice also had increased leptin levels as compared to controls. Leptin is a hormone that helps regulate energy expenditure and cycles with the circadian rhythm opposite to the cycle seen with glucocorticoids.

In the study discussion, Dr. Feldman noted that glucocorticoids act “as a synchronization signal to coordinate the circadian rhythm with energy balance. Taken together, our results imply that glucocorticoids regulate glucose homeostasis, in part, through direct control of the circadian clock, which in turn modulates leptin levels.” 

The study was published online October 5, 2009, in the Proceedings of the National Academy of Sciences (PNAS).

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PNAS research article

Stanford University Medical School press release

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