Melatonin-insulin interactions in type 1 diabetic rats

Introduction: Melatonin receptors (MT1 and MT2) in pancreatic β-cells and both the adenylyl-cyclase-cAMP and guanylyl-cyclase-cGMP pathways are prerequisites for the well-known suppression of insulin secretion by melatonin. We found reduced melatonin plasma levels in type 2 diabetic patients as well as in type 2 diabetic Goto Kakizaki (GK) rats, a model of non-insulin-dependent diabetes mellitus (NIDDM). Previous studies have investigated the differences in glucose, insulin and melatonin levels in type 2 diabetic rats and humans. Moreover, expression of pineal insulin receptor (InsR)- and arylalkylamine-N-acetyl-tranferase (AANAT)-mRNA has been monitored in type 2 diabetic rats. The present study investigated plasma glucose, insulin and melatonin, as well as the transcripts of InsR, AANAT, hydroxyindole-O-methyltransferase (HIOMT) and the ß1-adrenoceptor of pineal glands, using real-time RT-PCR in type 1 diabetic streptozotocin (STZ)- and insulin-dependent diabetes mellitus (IDDM) rats to compare these parameters with those of type 2 diabetic animals and patients.

Materials and Methods: For analyses the melatonin-insulin interactions in type 1 diabetic rats, insulin and melatonin plasma levels were measured in both STZ and IDDM rats by radioimmunoassay. Furthermore, the rate-limiting enzyme of melatonin synthesis, AANAT, and HIOMT, as well as the expression of pineal InsR- and β1-adrenoceptor-mRNA were analyzed in a diurnal series by real-time RT-PCR. In addition, insulin pellets were implanted in IDDM rats around day 60, the age at which they become diabetic, and the above listed parameters were analysed with and without insulin substitution.

Results: The results emphasize that decreased insulin levels or loss of insulin, which were observed both in 12 and 51 week old type 1 diabetic STZ rats, are combined with a statistically significant increase in melatonin levels. The same result was observed in approximately 60 day old male and female IDDM rats. Interestingly, the increased melatonin plasma levels in the IDDM rats were normalized after treatment with insulin implants. These results contradict those for type 2 diabetic individuals, which show decreased melatonin plasma levels. Astonishingly, the drastic metabolic disturbances are not accompanied by changes in diurnal rhythmicities.

Discussion: In contrast to type 2 diabetic individuals (GK rats and type 2 diabetic humans), type 1 diabetic STZ and IDDM rats showed a statistically significant increase in plasma melatonin levels. This increase in melatonin was normalized after substitution with insulin. Furthermore, in vitro investigations have shown that the perfusion of pineal glands with insulin reduces melatonin secretion, and the perfusion of both pancreatic islets and rat insulinoma cells (INS1) with melatonin also decreases insulin secretion. Finally, the transcription of pineal InsR, as well as that of the limiting enzyme of melatonin synthesis, AANAT, in type 1 diabetic STZ and IDDM rats was upregulated. Our observations suggest that there is a regulative interrelationship between pancreatic β-cells with their melatonin receptors and pinealocytes with their insulin receptors. This interrelationsship between melatonin and insulin may be significant for the genesis of diabetes.