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Did you know DNA influences your metabolic circadian clock and your risk of type 2 diabetes?

Body clocks, genes, sugar metabolism and the risk of type 2 diabetes

Have you ever wondered how a newborn baby learns the difference between night and day? Or why blue light from our smart devices affects our sleep? Or why the night shift is linked to gaining weight? Each of these questions leads us back to our body clock, also known as “circadian rhythm”, a mechanism that syncs our biological rhythms to the presence of light.

Today we have largely overcome our dependence on daylight. Neither the sunrise nor the sunset governs our lives. However, almost nothing in life comes without a price. We just might be paying for the luxuries that free us from light by enhancing our risk of metabolic disorders that shorten our lives. It’s been decades since the discovery of the first ‘clock’ gene. Now we know so much more about the army of genes that synchronize our body clock to the light-dark cycles. They coordinate our organs to match each other and link our metabolism to our sleep patterns. So it is not surprising that changes in two of these ‘clock’ genes, CRY2 and MTNR1B, increase our risk of type 2 diabetes.

All living organisms, from microscopic bacteria to 400-year-old oak trees, follow a circadian rhythm. This 24-hour internal cycle is synchronized to the rotation of the earth around its axis by “time givers”. Light, one such “time giver”, activates the central pacemaker of circadian rhythms within the suprachiasmatic nucleus (SCN) of our brain. This pacemaker helps regulate genes that control everything from our blood pressure, heart beat, hormone levels and metabolism, to learning, memory and behaviours.

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Our body clocks are the reason we feel jet lag, as our bodies need time to synchronize to an altered light-dark cycle. Thousands of years of evolution have aligned our eating habits to sleep and metabolism. During the day when we are awake, we consume food and store energy, while nighttime is reserved for sleep and fasting. Anything that disrupts this synchrony, or stimulates “metabolic jet lag”, like eating at night and shift work, is linked to an increased risk of metabolic diseases like type 2 diabetes.

At the core of circadian rhythms is a negative feedback loop, a self-regulating circuit that keeps our bodies ticking. Light turns on core genes, (e.g. CLOCK) in what is called the ‘activation arm’ of our body clocks. Among other gene interactions, the CLOCK gene activate genes in the inhibitory arm, such as the CRY2 gene.

The CRY2 gene acts back on CLOCK, and essentially shuts down the signal activated by light. The CRY2 gene is also responsible for turning off genes involved in the generation of new glucose (the primary sugar found in our blood) during the day. The rs11605924 variant of CRY2 is linked to higher blood sugar levels and increased risk of type 2 diabetes.

Interestingly, this link between CRY2 and glucose appears to depend on the time of the year and the availability of sunlight. The difference between the people with the risk version of CRY2 and those with the normal CRY2 was more significant in what was designated the dark season of the year (from November to April). One possibility is that rs11605924 reduces the activity of CRY2, which is more pronounced in fall and winter, because CRY2 expression is activated indirectly through light. Because of their involvement in metabolic diseases, drugs that can activate cryptochromes (encoded by the CRY genes) are actively being sought after as therapeutic options.

Melatonin, aka the ‘dark hormone’ released from the pineal gland in our brain, is another “time giver” that sets our biological clock. Melatonin production follows the light-dark cycle, where its levels are low during the day and high at night. It influences blood sugar levels by binding to the MT2 receptor (encoded by the MTNR1B gene). Melatonin-MT2 interactions decrease the secretion of insulin, and decrease the production of proteins that transport sugar into fat cells. So, it’s not surprising that a genetic variant of the MTNR1B gene called rs10830963 is linked to both increased blood sugar levels and the risk of type 2 diabetes. People with the rs10830963 risk allele make more of the MT2 receptor. This means even in the presence of low levels of melatonin, the receptor reduces insulin secretion, and slows the movement of sugar from our blood into fat cells.

If our health were a three-legged stool, sleep, the body clock and our metabolism would be each of its legs. They are so interdependent on each other that disrupting any one of these will tip the balance of the stool, making us more prone to disease. It will definitely be interesting to see how resetting our circadian clocks might boost our metabolic health, especially in the wake of the obesity and type 2 diabetes epidemic.

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