Melatonin Pathway and Atenolol-Related Glucose Dysregulation: Is There a Correlation?

Abstract

Lower melatonin level, melatonin receptor gene variations, and atenolol treatment are associated with glucose dysregulation. We investigated whether atenolol-related glucose and melatonin changes are correlated, and whether single nucleotide polymorphisms (SNPs) in melatonin candidate genes contribute to interindividual variation in glucose change. Hypertensive Caucasians (n = 232) from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study treated with atenolol for 9 weeks were studied. Urinary 6-sulfatoxymelatonin (aMT6s) was measured pre- and posttreatment and normalized to urinary creatinine. Pharmacogenetic effects on glucose change of 160 SNPs in 16 melatonin candidate genes were assessed with multiple linear regression. Atenolol was associated with increased glucose (1.8 ± 10.1mg/dl, P = 0.02) and decreased aMT6s (-4.5 ± 10.1 ng/mg, P < 0.0001). However, the aMT6s change was not correlated with post-atenolol glucose change. SNP rs11649514 in PRKCB was associated with glucose change (P = 1.0×10(-4)). PRKCB is involved in the melatonin-insulin regulatory pathway, and may be important in mediating clinically meaningful atenolol-related hyperglycemia.

Figure 1

Melatonin pathway and melatonin candidate genes. Squared symbol in the melatonin signaling cascade represents the involved proteins and the * symbol indicates protein encoded by melatonin candidate genes. Subtypes of the same protein family are not shown individually in the figure. AANAT, Aralkylamine N‐Acetyltransferase; ADRB1, Adrenoceptor Beta 1; ASMT, Acetylserotonin O‐Methyltransferase; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; DAG, diacylglycerol; ER, endoplasmic reticulum; IP3, Inositol trisphosphate; IP3R, Inositol trisphosphate receptor; MT, melatonin; MTNR1A, melatonin receptor 1A; MTNR1B, melatonin receptor 1B.

Figure 2

Glucose (a) and normalized aMT6s (b) changes after atenolol monotherapy in PEAR Caucasians (n = 194).

Figure 3

Correlation between change in normalized aMT6s and change in fasting glucose levels after atenolol monotherapy in PEAR Caucasians (n = 194). *Clinical covariates adjusted: age, gender, baseline glucose, baseline insulin, and BMI.

Figure 4

Atenolol‐related fasting glucose and aMT6s changes by PRKCB rs11649514 genotype in PEAR Caucasians under a dominate genetic model. (a) Glucose change in atenolol monotherapy group. (b) Glucose change in atenolol add‐on therapy group. (c) aMT6s change in atenolol monotherapy group (adjusted for age, gender, PC, and baseline aMT6s level). The adjusted mean and SE are presented.