Melatonin and Diabetes

The circadian rhytm – which makes us sleepy at night and active during the daytime – is controlled by the melatonin hormone secreted from the pineal gland in response to daylight. Every third person has a genetic variant in the melatonin receptor gene (MTNR1B), which increases the risk of Type 2 diabetes. Tuomi et al. showed in an intervention study in the PPP-Botnia Study (Prevalence, Prediction and Prevention of Diabetes) that 3-month treatment with melatonin led to a decrease in insulin secretion and an increase in plasma glucose in carriers of the risk variant.

This common variant (rs10830963) has previously been shown to increase the glucose level and decrease the insulin response to glucose, but the mechanism predisposing to diabetes has been unknown. In pancreatic islets from organ donors, Tuomi et al found the variant to be a so-called eQTL (expression quantitative trait locus), which means that the variant has a direct effect on the expression of MTR1B-receptor in pancreatic beta cells: carriers of one risk allele had twice and carriers of two risk alleles had four times as much MNTR1B messenger RNA compared with non-carriers (n=204). In an insulin-secreting cell-line, melatonin inhibited insulin secretion significantly more in cells over-expressing the MNTR1B gene than in control cells. This was mediated through decreased cAMP-formation. Similarly, in a knock-out mouse model lack of melatonin receptor led to increased insulin secretion.

According to the results from cells and mice this variant has a gain-of-function effect, which should also in humans result in a decreased insulin-response to glucose. Among non-diabetic persons, who were matched for age, sex and body-mass index, the glucose concentrations were higher and first-phase insulin secretion was lower in persons who were homozygous for the risk allele (n=23) compared with persons homozygous for the normal allele (n=22). After a 3-month treatment with melatonin (4 mg at night), insulin secretion had decreased and glucose level increased in both groups but significantly more in those with the risk variant (figure). The quality of sleep did not differ between the groups.

Pharmacological melatonin treatment is very common nowadays and it has been considered quite harmless as melatonin has much fewer side-effects compared with the traditional sleeping pills.  This study showed, however, that even a short melatonin use affects the glucose homeostasis. Maybe at least the risk variant carriers should avoid longer use of melatonin – at least if they have other risk factors for type 2 diabetes.

Original study:

Tuomi T, Nagorny CL, Singh P, Bennet H, Yu Q, Alenkvist I, Isomaa B, Östman B, Söderström J, Pesonen AK, Martikainen S, Räikkönen K, Forsén T, Hakaste L, Almgren P, Storm P, Asplund O, Shcherbina L, Fex M, Fadista J, Tengholm A, Wierup N, Groop L, Mulder H. 11. Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes. Cell Metab 23: 1067-1077, 2016

 

Figure: The effect of melatonin treatment in persons with either risk (GG; n=23) or non-risk (CC; n=22) genotype of the MTNR1B variant during an oral glucose tolerance test. CIR (corrected insulin-response) reflects the ratio of insulin and glucose concentrations at 30 min after ingestion od glucose. (**P<0.01, ***<0.001).