Abstract and Introduction
Context: Glucose homeostasis is under circadian control through both endocrine and intracellular mechanisms, with several lines of evidence suggesting that melatonin affects glucose homeostasis.
Objective: To evaluate the acute in vivo and in situ effects of melatonin on secretion of the incretin hormones, glucagon-like-peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), and their impact on β-cell insulin secretion.
Design: A human randomized, double-blinded, placebo-controlled crossover study combined with a confirmatory in situ study of perfused rat intestines.
Setting: Aarhus University Hospital.
Methods: Fifteen healthy male participants were examined 2 × 2 times: an oral glucose tolerance test (OGTT) was performed on day 1 and an isoglycemic IV glucose infusion replicating the blood glucose profile of the OGTT day was performed on day 2. These pairs of study days were repeated on treatment with melatonin and placebo, respectively. For the in situ study, 6 rat intestines and 4 rat pancreases were perfused arterially with perfusion buffer ± melatonin. The intestines were concomitantly perfused with glucose through the luminal compartment.
Results: In humans, melatonin treatment resulted in reduced GIP secretion compared with placebo (ANOVA P = 0.003), an effect also observed in the perfused rat intestines (ANOVA P = 0.003), in which GLP-1 secretion also was impaired by arterial melatonin infusion (ANOVA P < 0.001). Despite a decrease in GIP levels, the in vivo glucose-stimulated insulin secretion was unaffected by melatonin (P = 0.78).
Conclusion: Melatonin reduced GIP secretion during an oral glucose challenge in healthy young men but did not affect insulin secretion. Reduced GIP secretion was confirmed in an in situ model of the rat intestine.
Melatonin is a modified amino acid hormone produced by the pineal gland. Its secretion follows a circadian rhythm, with peak levels during the night. It is involved in sleep, thermoregulation, circadian rhythm, and glucose homeostasis,[1–3] but direct effects of melatonin on glucose homeostasis in vivo remain to be unravelled. Melatonin exerts its actions by binding to 2 widely expressed Gi protein-coupled receptors, melatonin receptor 1a (MTNR1A) and melatonin receptor 1b (MTNR1B). The MTNR1A and the MTNR1B genes encode these receptors, and both receptors are present in the endocrine pancreas.[4,5] Genome-wide association studies have revealed a single-nucleotide polymorphism, rs10830963 in the MTNR1B gene, which is associated with unfavorable glucose homeostasis and an increased risk of developing type 2 diabetes mellitus.[6–10] However, only a few clinical studies have addressed the direct acute effects of melatonin on glucose homeostasis.[11–14] Three studies report impaired glucose tolerance in postmenopausal as well as young women during an oral glucose tolerance test (OGTT).[11–13] This effect was greater in young women with the rs10830963 risk allele compared with homozygous wild-type carriers. The underlying mechanisms could involve a combination of reduced insulin sensitivity, a direct impairment of β-cell function, or reduced secretion and/or effect of the incretin hormones.
The incretin effect is defined as the increase in insulin secretion following an oral glucose challenge compared with an IV glucose challenge with similar glucose levels.[15,16] The effect is primarily mediated via the intestinal K cell-derived glucose-dependent insulinotropic peptide (GIP) and the intestinal L-cell-derived glucagon-like-peptide 1 (GLP-1).[17,18] The incretin effect is responsible for up to 70% of the insulin secretion following ingestion of glucose and is thus essential for normal glucose homeostasis. The incretin effect is, under experimental conditions, assessed using an OGTT followed by an IV isoglycemic glucose infusion on 2 separate study days, as previously described.
In vitro experiments with incubation of pancreatic β-cells with melatonin have been equivocal with both stimulatory and inhibitory effects on insulin secretion,[4,20–22] and measures of insulin sensitivity derived from oral and IV glucose tolerance tests in human studies have revealed a reduction by 26% to 44% in insulin sensitivity following melatonin administration.[11,12] Recently, we found no effects of melatonin on β-cell function during an IV glucose tolerance test and a 9% suppression of insulin sensitivity by melatonin during a hyperinsulinemic-euglycemic clamp in healthy young men. However, knowledge of the effect of melatonin on GIP and GLP-1 secretion is limited despite the importance of these hormones for glucose tolerance combined with the presence of melatonin receptors in the gastrointestinal tract.[23,24]
Thus, we hypothesized that the observed acute impairment of glucose tolerance by melatonin[11–13] could partly be mediated through a reduced incretin effect either by reduced GLP-1 and/or GIP secretion or by a reduced effect of GLP-1 and/or GIP on glucose-stimulated insulin secretion. We studied this in human experimental studies, but also used an in situ perfused rat intestine to investigate the direct effects of melatonin on the K and L cells responsible for incretin secretion. Likewise, we applied an in situ perfused rat pancreas to assess the isolated effect of melatonin on glucose-stimulated insulin secretion in the pancreas.
J Clin Endocrinol Metab. 2021;106(12):e5109-e5123. © 2021 Endocrine Society