The results of this study showed that the fasting plasma glucose levels, HbA1c and BMI values were significantly higher in patients with DR+C than in the DM+C and C groups. When the Alarin results were examined, the plasma Alarin levels were seen to be significantly higher in the DM+C and DR+C groups compared to the C group (p=0.006, p<0.001). In vivo and in vitro animal studies have shown that Alarin reduced insulin resistance and lowered increased insulin and glucose levels [17, 18].
In vivo studies have also reported that Alarin may be released in response to metabolic stress factors such as abdominal obesity, insulin resistance, dyslipidemia, hyperglycemia, and hypertension. . In patients with metabolic syndrome and obesity, Alarin levels have been determined to be higher than those of control groups. There has been observed to be a compensatory elevation in Alarin levels in response to oral glucose intake. It has been emphasized that high Alarin levels may be related to resistance to Alarin with a mechanism similar to insulin resistance. . The patients in our study consisted of patients with a body mass index of 30 and above, with metabolic syndrome-like findings.. The elevated Alarin levels determined in the DM+C and DR+C of the current study could be associated with both a compensatory response to chronic hyperglycemia and with potential Alarin resistance.
In mice, Alarin injection into the central nervous system or peripheral administration causes orexigenic behavior and weight gain, as well as a decrease in plasma insulin and glucose levels [17, 18]. Reduced glucose intake to skeletal muscle is the key factor in insulin resistance. Both central and peripheral administration of Alarin has been shown to increase the passage of glucose to tissues, especially skeletal muscle, by the GLUT 4 pathway . In addition, the effects of Alarin on insulin sensitivity have been found to emerge by reducing RBP4 and increasing adiponectin levels . Alarin’s orixogenic effects are thought to be NPY-mediated. However, no Alarin-specific receptor revealing the central effects of Alarin has been determined . It is known that chronic hyperglycemia can cause diabetic retinopathy through several mechanisms. The elevated Alarin levels in the current study may be associated with chronic hyperglycemia. However, high Alarin levels not at a level to prevent hyperglycemia, may be related to resistance to Alarin as stated in previous studies, predominance of the orexigenic effect or as yet unrevealed specific Alarin receptor-mediated complex mechanisms. Therefore, although the Alarin levels were high in current study, they were not at an effective level to prevent the development of diabetic retinopathy. Further studies of Alarin-specific receptors and effect mechanisms could reveal the potential for Alarin to be used especially in hyperglycemia treatment.
Alarin immunoreactivity has been determined in human ocular epithelial cells (cornea, conjunctiva, ciliary body), ocular blood vessels (iris, retina, choroid) and neurons (retina and choroid) . It has been reported that Alarin may function as a neuropeptide in interaction with other neurotransmitters and neuropeptides, which probably have neuromodulator functions in the choroid and retina. . Alarin, which has been found in the iris blood vessels and ciliary body, is considered to have a role in the immune defense of the eye, as well as maintaining the function of the corneal endothelium in the anterior chamber, with neurotransmitter and neuropeptide-like actions . The activity of alarin detected around retinal and choroidal vessels suggests that it may be important in ocular blood flow hemostasis due to the change in blood vessel diameter. Alarin shows a dose-related vasoconstriction, anti-edema and anti-inflammatory effect following subcutaneous injection in the skin and and this effect supports its potential effects on retinal vessels . In the current study, the Alarin levels in the aqueous humour were determined to be significantly high in the DR+C group compared to the DM+C and C groups (p=0.011, p=0.006). High levels of Alarin in aqueous humor in the current study suggest that Alarin may play a compensatory role in diabetic retinopathy, which is associated with changes in retinal microvascular structure, macular edema, and inflammation. Future studies with Alarin, we believe, will be important in determining whether the vasoconstrictor, anti-edema, and anti-inflammatory effects of this molecule can be used to treat diabetic retinopathy.
When the Adipsin results in the current study were examined, the Adipsin levels in the DR+C group and DM+C group were determined to be statistically significantly lower than those of the C group (p<0.001, p<0.001). Adipsin is an important molecule, expressed from adipose tissue, which has an effect on glucose and lipid metabolism. Adipsin provides complement factor mediated insulin secretion from pancreatic beta cells, transfer of glucose from plasma to tissue and storage by converting to triglycerides in tissue . In mice with defective Adipsin gene, Lo et al determined reduced glucose tolerance and insufficient insulin secretion. As a result of treatment of diabetic db/db mice with vectors expressing Adipsin, there was seen to be an improvement in glucose tolerance and a reduction in FPG. At the same time, fasting and glucose-induced insulin levels increased. Even if beta cell function was insufficient, the Adipsin levels were determined to be low . Adipsin levels have been determined to be significantly low in db/db and ob/ob mice with high glucose levels and a decrease in Adipsin levels has been determined in a hyperinsulinemic and hyperglycemic environment created with continuous glucose infusion [21, 22]. In a study by Banoy et al, it was emphasised that high Adipsin levels reduced the risk of developing diabetes in middle-aged adults . When hyperglycemia and impaired insulin expression causing diabetic retinopathy are considered, the low Adipsin levels are consistent with literature and are an expected finding. Therefore, we believe Adipsin could be a potential treatment option for reducing the severity of diabetic retinopathy and its complications.
There are several conflicting results in literature related to Adipsin levels in obese patients. BMI values have been reported to be ≥35 in obese patients determined with high Adipsin levels and this elevation has not been determined in those with a lower BMI . In a study by Wang et al, Adipsin levels were determined to be low and insulin resistance was high in patients with BMI ≥25 . It has also been suggested that this elevation could be due to subcutaneous adipose tissue in patients with high Adipsin levels, and Adipsin levels have not been found to be high in those with visceral adipose tissue . In addition, it has been reported that as a result of persistent glucose elevations in type 2 diabetes patients in particular, compensation in adipose tissue is impaired and Adipsin levels could decrease . Besides the reasons stated above, these differences can be affected by many factors such as the duration of diabetes, racial differences, patient selection criteria, and method of determination . The patients included in the current study were obese with mean BMI of 32.76±1.68 in the DM+C group and 34.76±2.66 in the DR+C group. The Adipsin levels were determined to be low in the obese patients in the current study. It suggests that there may be a defect in the compensatory release of Adipsin from the adipose tissue despite the increased glucose levels to cause diabetic retinopathy, and that pancreatic beta cell function may be low in our patient group. The improvement in the metabolism of Adipsin as a result of the decrease in the BMI may constitute an important factor in the treatment of diabetes and its complications.
Adipokine receptors have been determined in the choroid, iris, ciliary body, and cornea . Adiponectin treatment of laser-induced choroidal neovascularization in rats resulted in a reduction in vascular endothelial growth factor levels and a regression in neovascularization. . Ricker et al. compared cases of recurrent retinal detachment due to proliferative vitreoretinopathy to cases of rhegmatogenous retinal detachment in their study, and reported no significant differences in Adipsin levels in subretinal fluid in both groups . These studies demonstrate that Adipsin could have a role in physiological and pathological processes in the eye. In the current study, the Adipsin levels in the aqueous humour samples taken from the anterior chamber were determined to be significantly high in the DR+C and the DM+C compared to the C group. The aqueous Adipsin levels were also determined to be higher than in plasma. When it is considered that adiponectins have a role in wound healing and inflammatory response, Adipsin could have a role in the pathogenesis of diabetic retinopathy or in the local response to diabetic retinopathy. However, there is a need for further studies to determine whether or not Adipsin can be used locally in the eye in the treatment of diabetic retinopathy.
There were some limitations to the current study, primarily the relatively small number of patients and the cross-sectional design of the study.