Retinal diseases are a leading cause of visual loss and blindness, affecting a significant proportion of the population worldwide and having a detrimental impact on quality of life, with consequent economic burden. The retina is highly metabolically active, and a number of retinal diseases are associated with metabolic dysfunction. To better understand the pathogenesis underlying such retinopathies, new technology has been developed to elucidate the mechanism behind retinal diseases. Metabolomics is a relatively new “omics” technology, which has developed subsequent to genomics, transcriptomics, and proteomics. This new technology can provide qualitative and quantitative information about low-molecular-weight metabolites (M.W. < 1500 Da) in a given biological system, which shed light on the physiological or pathological state of a cell or tissue sample at a particular time point. In this article we provide an extensive review of the application of metabolomics to retinal diseases, with focus on age-related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), glaucoma, and retinitis pigmentosa (RP).

Objective: Melatonin (Mel) and its receptors are promising for glycemic control in patients with type-2 diabetes mellitus (T2DM) and its complications, but there is significant heterogeneity among studies. This study aims to investigate the effects of Mel receptor agonist Neu-P11 on glucose metabolism, immunity and islet function in T2DM rats. Methods: In this study, SD rats were treated with high fat diet and streptozotocin (STZ) to establish T2DM model. Glucose oxidase method was used to measure blood glucose level. Glucose and insulin tolerance tests were used to assess glucose metabolism. HE staining was used to observe the pancreatic tissue injury. The apoptosis of islet β cells was analyzed by TUNEL and insulin staining. ROS levels and immune cell expression were analyzed by flow cytometry. IF was used to analyze the activation of microglia. The IgA, IgG, IgM, TNF-α, IL-10, IL-1β, IFN-γ, C-peptide and Insulin levels were determined by ELISA. The expression of CD11b, CD86, cleaved caspase3, p21, and P16 proteins were analyzed by western blot. Results: The results showed that the blood glucose level increased, insulin resistance occurred, spleen coefficient and ROS levels increased, humoral immunity in peripheral blood decreased, and inflammation increased in the model group compared to the control group. After Mel and Neu-P11 treatment, the blood glucose level decreased significantly, insulin sensitivity improved, spleen coefficient and ROS levels decreased, humoral immunity in peripheral blood enhanced, and inflammation improved in T2DM rats. Brain functional analysis of T2DM rats showed that microglia cells were activated, TNF-α and IL-β levels were increased, and IL-10 levels were decreased. Mel and Neu-P11 treatment reversed these indexes. Functional analysis of islet in T2DM rats showed that islet structure inflammation was impaired, islet β cells were apoptotic, p21 and p16 protein expressions were increased, and blood C-peptide and insulin were decreased. Mel and Neu-P11 treatment restored the function of pancreatic β cells and improved the damage of pancreatic tissue. Conclusion: Melatonin and its receptor Neu-P11 can reduce blood glucose level, enhance humoral and cellular immunity, inhibit microglia activation and inflammation, and repair islets β cell function, improve the characterization of T2DM related diseases. Objective: Melatonin (Mel) and its receptors are promising for glycemic control in patients with type-2 diabetes mellitus (T2DM) and its complications, but there is significant heterogeneity among studies. This study aims to investigate the effects of Mel receptor agonist Neu-P11 on glucose metabolism, immunity and islet function in T2DM rats. Methods: In this study, SD rats were treated with high fat diet and streptozotocin (STZ) to establish T2DM model. Glucose oxidase method was used to measure blood glucose level. Glucose and insulin tolerance tests were used to assess glucose metabolism. HE staining was used to observe the pancreatic tissue injury. The apoptosis of islet β cells was analyzed by TUNEL and insulin staining. ROS levels and immune cell expression were analyzed by flow cytometry. IF was used to analyze the activation of microglia. The IgA, IgG, IgM, TNF-α, IL-10, IL-1β, IFN-γ, C-peptide and Insulin levels were determined by ELISA. The expression of CD11b, CD86, cleaved caspase3, p21, and P16 proteins were analyzed by western blot. Results: The results showed that the blood glucose level increased, insulin resistance occurred, spleen coefficient and ROS levels increased, humoral immunity in peripheral blood decreased, and inflammation increased in the model group compared to the control group. After Mel and Neu-P11 treatment, the blood glucose level decreased significantly, insulin sensitivity improved, spleen coefficient and ROS levels decreased, humoral immunity in peripheral blood enhanced, and inflammation improved in T2DM rats. Brain functional analysis of T2DM rats showed that microglia cells were activated, TNF-α and IL-β levels were increased, and IL-10 levels were decreased. Mel and Neu-P11 treatment reversed these indexes. Functional analysis of islet in T2DM rats showed that islet structure inflammation was impaired, islet β cells were apoptotic, p21 and p16 protein expressions were increased, and blood C-peptide and insulin were decreased. Mel and Neu-P11 treatment restored the function of pancreatic β cells and improved the damage of pancreatic tissue. Conclusion: Melatonin and its receptor Neu-P11 can reduce blood glucose level, enhance humoral and cellular immunity, inhibit microglia activation and inflammation, and repair islets β cell function, improve the characterization of T2DM related diseases.

It is generally accepted that a major risk factor of type 2 diabetes mellitus (T2DM) is insulin resistance and is often associated with obesity [1]. Apelin (expressed in adipose tissue) appears as a beneficial adipokine with anti-diabetic and anti-obesity properties [2]. Clock is a large and complex gene encoding a novel member of the basic helix-loop-helix/Per-ARNT-Sim protein family of transcription factors. Circadian clocks can regulate metabolic homeostasis and clock disruption leads to obesity and the metabolic syndrome [3]. Melatonin (Mel) is an integral part of the homeostatic mechanism in the body. It is best known as a regulator of seasonal and circadian rhythms, with high expression level during the night and low level during the day. Interestingly, insulin levels are also adapted to day/night changes through Mel-dependent synchronization. Mel may influence diabetes and be associated with metabolic disturbances by regulating insulin secretion [4]. Luzindole is the non-specific Mel receptor antagonist that can block some functions of Mel [5]. Although Mel has a wide range of biological effects, studies have found that once it gets into human body, its metabolism can be very fast, with a half-life of 20–30 min. Therefore, apparent effects cannot be achieved from direct administration of this medicine. Besides, the extraction and synthesis of Mel are relatively difficult, and some side effects may arise if its dose is too high. Neu-P11 is a new type of non-selective agonist of Mel [6]. It has the following characteristics: it can be synthesized relatively easily in vitro; its effective time can be longer with fewer side effects; it can substitute Mel to interact with its receptors, and sequentially play a wide range of biological roles. The aim of the present study was to explore the mechanism of the Mel and its receptor agonist Neu-P11 and the change of clock/apelin in insulin-resistant 3T3-L1 adipocytes.

The prevalence of Type 2 diabetes (T2D) has been globally increased since the last decade. T2D is a condition of relative insulin insufficiency, in which hyperglycemia develops when the insulin secretory capacity of β-cells is no longer sufficient to meet the insulin requirement in the setting of insulin resistance [1]. Previous studies have shown that there is a close correlation between T2D and insulin receptor substrate-1 (IRS-1) levels, and that lack of expression or abnormal phosphorylation of IRS-1 can lead to insulin resistance [2]. Phosphoinositide 3-kinase (PI3K) plays a key role in insulin signaling and its activity has been shown to be blunted in tissues from T2D subjects. PI3K activation is critical for insulin-mediated metabolic effects such as increased glucose uptake and glycogen synthesis [3]. Glycogen synthase kinase-3β (GSK3β), a downstream target of insulin signaling, is activated by phosphorylated (p) Akt [4]. Phosphorylation by p-Akt inhibits the activity of GSK3β [5]. GSK3β phosphorylation and inactivation are considered to be important mechanisms of cell survival [6]. Melatonin (Mel) is a circulating hormone that is predominantly released from the pineal gland [7]. Some studies suggest that Mel may potentially play a role in diabetes and its associated metabolic disturbances by regulating insulin secretion. Luzindole is a nonspecific Mel receptor antagonist that can block some Mel functions [8]. Although Mel has an extensive range of biological effects, studies have revealed that it is rapidly metabolized with a half-life of 20–30 min once it gets ingested in humans. Therefore, the effect of Mel cannot be studied from direct administration of this drug. Moreover, extraction and synthesis of Mel is complicated and a high dose of Mel is associated with side effects. Neu-P11 is a novel type of nonselective agonist of Mel. It has several characteristics including the ease with which it can be synthesized in vitro and administered effectively for a longer time with fewer side effects. It can also substitute for Mel to interact with its receptors and consequently has an extensive range of biological actions [9].