4. Discussion
hypoglycemia, hypersensitivity, T2DM, insomnia
EVENT, DISORDERS, HYPOGLYCEMIA, TYPE 2 DIABETES, HYPERSENSITIVITY
This was the first randomized, double-blind, placebo-controlled, crossover study to assess the role of melatonin on glycemic variability in T2DM patients. In this work, we were able to demonstrate that melatonin of 3 mg, taken at 9:00 p.m., compared to the placebo, increased the glycemic variability in these patients on the seventh day (D7). In addition, there was a greater amplitude (delta) of glycemic variability between post-dinner and pre-breakfast glycemia between D6 and D7 in the patients who used melatonin. There was no difference in the coefficient of glycemic variability between the placebo and the melatonin. These results are different from what was initially hypothesized in the study. Melatonin is considered a hormone that regulates circadian rhythm. We expected, therefore, that its use could reduce glycemic variability in patients with type 2 diabetes and not increase it. How can we explain the results found here?Some theories may explain the positive increase in melatonin between pre- and post-breakfast on the seventh day. The effects of exogenous melatonin expected in this study are those related to the absence of this hormone during the day. Capillary blood glucose levels were measured during the day, and melatonin was taken at night. Prospective effects of melatonin occur when its concentrations are low or undetectable. One type of prospective effect of melatonin is proximal, which occurs after this substance reduces its concentration in the morning. The nocturnal inhibitory effect of melatonin on G protein-coupled receptors ends in the morning. This deactivation of the receptor generates a rebound effect of hypersensitivity in the intracellular pathway of adenyl cyclase/cAMP/PKA/CREB [Higher doses of melatonin used during the night may lead to a residual effect of this hormone beyond the nighttime period [The second result of this work demonstrated an increase in the amplitude between glycemia of day 6 of post-dinner and day 7 of pre-breakfast. It can be explained by the prospective distal effects of melatonin. Melatonin acts directly to suppress the activity of the Clock/Bmal1 complex. A prolonged inhibitory effect on this complex due to a non-physiological effect of exogenous melatonin could lead to an abnormal synchronization of the biological clock, making the variation in blood glucose during the night erratic.Another important factor that may influence the results of glycemic variability in studies on melatonin and T2DM is the melatonin receptor polymorphism MTNR1B rs10830963. Some works demonstrate that the mutation of this common receptor in patients with T2DM may predispose them to a worse glycemic response with the use of melatonin [The variation in the glycemia delta (post minus pre-breakfast) on the seventh day of the study showed a In this work, we cannot define whether a greater positive variation in blood glucose at breakfast after 7 days of using melatonin (3 mg) was a positive or negative event. As the glycemic variability of our patients was small, a statistically significant increase in postprandial glycemia in the morning may not represent an inadequate clinical result. In fact, the physiological result is that postprandial glycemia has an elevation of at least one standard deviation. A lower elevation may represent a problem for T2DM patients, exposing them to the risk of hypoglycemia by the frequent use of medications with greater hypoglycemic power. In this sense, we can hypothesize that melatonin supplementation may have reestablished a more physiological pattern of glycemic elevation in these patients, with eventual benefit from the point of view of protection against hypoglycemia. A greater amplitude of variation of post-dinner glycemia on D6 compared to pre-breakfast on D7 can be considered a negative result of the use of melatonin. Glucose variation with an average of more than 50 mg/dL during melatonin use is considered an inadequate glucose variation.Theoretically, exogenous melatonin could be incorporated into the therapeutic arsenal of patients with insomnia. As we age, these disorders become more prevalent, which could be associated with the decline in serum levels of this hormone as well as its physiological cyclicity [Our work presents some critical points. The coefficient of glycemic variability, both when the patients used the placebo and when they used melatonin, was similar and small, less than 36% in most cases. These data may be related to the fact that the patients had a glycemic average practically at the target, as verified by the general average of HbA1C, which was around 7.3%. The low glycemic variability observed in our study may have concealed a potential effect of melatonin on glucose variation. Another criticism of our study is the fact that the duration of melatonin use was only 7 days. Prolonged use may lead to different outcomes regarding glycemic variability. Finally, we did not assess the presence or absence of the MTNR1B gene mutation or the melatonin concentration of our patients. There was a simple assumption that they would have this mutation more often and would be melatonin-deficient because they have T2DM.The positive points of this study are also relevant. The fact that it is a double-blind, placebo-controlled, randomized study gives the results of this study greater methodological validity. Furthermore, the results found in this study can be explained by the physiology of melatonin. Finally, this study was carried out in a real-life context. For example, as the aim of the study was to assess the chronobiotic effects of melatonin on glycemic variability, no guidance on dietary timing was given to patients. This implies that the results of this can therefore be used in everyday clinical practice.