Regulation of TNF[alpha]-induced insulin resistance by melatonin and PDZD2/sPDZD2

Abstract

Type 2 diabetes mellitus (T2DM) is a global public health problem affecting millions of people. T2DM is a state of hyperglycemia, characterized by peripheral insulin resistance and dysfunction of β cells. Factors such as genetics, obesity and disruption of circadian cycle have been reported to associate with T2DM.

Melatonin and its signaling have been shown to implicate in insulin resistance and T2DM for years. Therapeutic potential of melatonin in combating insulin resistance and T2DM was emerged by a previous study in which melatonin was able to rescue adipose insulin resistance provoked by free fatty acids. Owing to the heterogeneity of T2DM, efficacy of melatonin may vary. Besides, PDZ domain-containing 2 (PDZD2) and its secreted from sPDZD2, whose roles were studied extensively in pancreas, have been shown to regulate the function of adipocytes. A recent transcriptomic study reported a down-regulation of PDZD2 in insulin resistance, suggesting a possible involvement of PDZD2/sPDZD2 in adipose insulin resistance. Yet roles of PDZD2/sPDZD2 in adipocyte function, insulin resistance and T2DM are still poorly understood. The current study aimed to explore the respective roles of melatonin and PDZD2/sPDZD2 in insulin resistance provoked by TNFα in differentiated 3T3-L1 MBX adipocytes, and for the first time their cross-interaction on adipose insulin sensitivity.

In the current study, it was found that melatonin rescued TNFα-induced insulin resistance in adipocytes to a normal level, as reflected by a 40% increase in phosphorylation of PKB/Akt. This rescue effect was further enhanced by inhibition of PKC (although at a marginally statistically insignificant level) but not PKA, suggesting a PKC-dependent mechanism might involve. Besides, expression of PDZD2 gene was down-regulated by 50% in a state of TNFα-induced insulin resistance in adipocytes. On the contrary, expression of PDZD2 protein was up-regulated by 200% in TNFα-induced adipose insulin resistance. These together suggested an abnormal expression of PDZD2 in the setting of insulin resistance. Interestingly, effect of sPDZD2 on adipose insulin sensitivity was glucose-dependent. sPDZD2 exerted no observable effect on adipose insulin sensitivity at a physiological level of glucose (5.5 mM), but impaired adipose insulin sensitivity in a high glucose environment (25.0 mM). Surprisingly, sPDZD2 interacted positively and synergistically with DMSO on adipose insulin sensitivity. Presence of melatonin abolished this synergistic interaction between sPDZD2 and DMSO only in a high glucose environment, restoring adipose insulin sensitivity to a control level. This demonstrated a glucose-dependent interaction between sPDZD2 and melatonin.

Taken together, the current study highlighted the therapeutic potential of melatonin against TNFα-induced adipose insulin resistance, shedding lights to novel applications of melatonin against insulin resistance. Abnormal expression of PDZD2 might be one possible cause of insulin resistance and probably T2DM. The glucose-dependent action of sPDZD2 and its synergistic interaction between DMSO on adipose insulin sensitivity might facilitate better understanding of the complex mechanisms of insulin resistance. The current study provided new perspectives on insulin resistance and melatonin-based drugs against T2DM.