Plasma Adipsin as a Biomarker and Its Implication in Type 2 Diabetes Mellitus

Introduction

Diabetes mellitus is one of the most common metabolic disorders characterized by hyperglycemia.¹ It occurs due to absolute or partial lack of insulin and/or insulin resistance.² Diabetes mellitus is a common public health threat affecting millions of people in the world of all ages, gender, race and ethnic groups.³ The burden of DM is increasing throughout the world, and around 80% of diabetes deaths occur mainly in low and middle-income countries.⁴ Based on the pathogenesis of hyperglycemia, most patients with DM are either Type 1 (insulin dependent) or Type 2 (non-insulin dependent).⁵ Among which, T2DM has been most commonly reported (90–95% of cases).⁶

According to World Health Organization (WHO) report in 2019, DM affects around 422 million adults in the world.² In 2013, DM was the seventh leading cause of death (causing 74.9 thousand deaths) and it is the eighth leading cause of disability (causing 1.85 million years living with disability).⁷ It is also estimated that diabetes will affect 642 million in 2040.⁸ Even though the prevalence of DM diagnosed patients is high, nearly half of them are unaware of their disease.⁹ On the other hand, according to the International Diabetes Federation, T2DM contributes for the sufferings of about 415 million people in the world; and it is becoming increasing in its prevalence.¹⁰

The pathologic hallmarks of T2DM are mainly abnormal insulin secretion and increased insulin resistance. There is also a decrease in the functional pancreatic β-cell mass over time upon the progression of the disease condition.¹¹ T2DM is associated mainly with obesity, which results in impaired insulin mediated glucose uptake due to intracellular impairment of insulin signaling. There is also a significant reduction in glucagon-like peptide-1 secretion, which is secreted after food ingestion and increases insulin secretion, in patients with T2DM.¹²

If left untreated, DM is associated with devastating short-term (diabetic ketoacidosis and hyperosmolar hyperglycemic state) and long-term (retinopathy, nephropathy, neuropathy and lower limp amputation) complications.^5,13,14 Moreover, different cardiovascular and endocrine abnormalities are associated with DM, which can affect the quality of life of patients.^8,15

The diagnosis of DM has been varied from time to time. However, recurrent or persistent hyperglycemia is used to characterize DM. Different diagnostic parameters were used to assess patients with DM including, fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) and Hemoglobin Alc (HgA1c).^16,17 However, these diagnostic tools are associated with reduced sensitivity and/or specificity to detect diabetes in its early stage.¹⁸ To overcome such problems different newer diagnostic methods were developed by targeting endogenous proteins such as Leptin, TNF-alpha, C-reactive protein (CRP),¹⁹ Netrin,²⁰ Thioredoxin-interacting protein (TXNIP).³ But, these novel methods have been also associated with increased cost.²¹ Hence, the present review is used to assess the role of Adipsin as a novel diagnostic parameter and its implication in T2DM.

Overview of Adipsin

Adipose tissue is no longer regarded as a passive site for energy accumulation in the form of triacylglycerols. Nevertheless, it is also a vital endocrine gland that secretes many bioactive molecules.^22,23 Adipokines (or adipocytokines) can be defined as a group of more than 600 bioactive molecules made from adipose tissue that acts as paracrine and endocrine hormones.^23,24 Adipokines are involved in maintaining varieties of processes such as, appetite and satiety, energy expenditure activity, endothelial function, blood pressure, hemostasis, adipogenesis, insulin sensitivity, energy metabolism in insulin-sensitive tissues, fat distribution and insulin secretion in pancreatic β-cells.^25–27 Adipsin, also termed as complement factor D, is one of the adipokines which was the first described adipokine.²⁸ Adipsin is a member of the serine protease family with a 28-kilo Dalton protein found in 3T3 adipocytes.²⁹ Adipsin maintain adipose tissue homeostasis and increases insulin secretion in response to glucose. Additionally, it catalyzes C3a (an active form of component 3, C3) production by controlling the alternative complement pathway causing an increase in insulin secretion from the pancreas.^30,31

Adipsin is important in the formation of the C5–C9 membrane attack complex and in the generation of various signaling molecules, comprising the anaphylatoxins, complement 3a (C3a) and C5a.³⁰ In the synthesis, these signaling molecules, first complement factor B is cleaved by Adipsin and these catalyze the formation of C3 convertase and it leads to the hydrolysis cascade that produces different complement fragments including C3a, C3b, C5a and C5b.³² It was reported that familial C3 deficiency is associated with obesity and metabolic diseases, and C3a levels are risk factors for DM.³³ The overall effect of Adipsin on insulin secretion is summarized in Figure 1.

Figure 1 Effect of adipsin on insulin secretion.

Preclinical and Clinical Studies on the Serum Levels of Adipsin in Type 2 Diabetes Mellitus

Circulating Adipsin levels are negatively correlated with T2DM. Various experimental and clinical studies showed that plasma concentrations of Adipsin is decreased in humans and animals with DM compared to the normal control group as indicated in the table below (Table 1).

Table 1 Serum Levels of Adipsin in Type 2 Diabetes Mellitus

Implications of Adipsin in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is characterized by an increase in blood glucose level caused by pancreatic β-cell failure and/or insulin resistance.⁴³ Adipsin is reported to maintain β-cell function, which is important to boost insulin secretion.³⁰ According to a study by Gómez-Banoy et al³¹, restoration of Adipsin in diabetic mice did not merely improve hyperglycemia, rather it also preserves β-cell mass by improving β-cell survival and maintaining β-cell transcriptional identity. Additionally, increased Adipsin level is associated with lower risk of diabetes in humans.³¹

Patients with newly diagnosed diabetes and known T2DM show a decreased levels of Adipsin; and there is an independent negative association between Adipsin and HOMA-IR. It was concluded that the negative association might be due to the expression of inflammatory cytokines like IL-17 in T2DM.³⁶ The plasma concentrations of Adipsin were reduced in T2DM patients with impaired glucose tolerance; which is associated with the first‐phase insulin secretion of pancreatic β‐cells and glucose metabolism. This was evidenced by the positive correlation between serum Adipsin and HOMA‐β.²⁹

In obesity complicated with T2DM, there is a disturbance in the relationship between Adipsin and leptin. An increase in Adipsin production in obesity can be regarded as a compensatory response for normalizing the parameters of the lipid and carbohydrate metabolism.³⁷

Unlike other insulin secretagogues, various preclinical studies showed that Adipsin replenishment in diabetic mice reduces hyperglycemia, and raises insulin levels while maintaining β-cells by stopping dedifferentiation and death. In recent times, Adipsin has been found capable of promoting insulin secretion and stabilizing plasma glucose levels. In addition, diabetic mice treated with Adipsin showed significant reductions in fasting plasma glucose and increased glucose clearance, while fasting and glucose-induced insulin levels were also improved.^27,30 Adipsin could also stimulate glucose transport for triglyceride accumulation in adipose tissue and inhibits lipolysis. It is justified that free fatty acids could exacerbate pancreatic β-cell failure and insulin resistance.³⁷

On the other hand, the negative correlation between Adipsin and insulin resistance in diabetic rats implies that Adipsin might increase insulin sensitivity and reduce glucose intolerance in T2DM.³⁹ As explained by Lo et al, the possible mechanism by which Adipsin increases insulin secretion is via generating C3a. C3a acts on islets of the pancreas by augmenting its receptor (C3aR1) and inhibiting ATP sensitive K⁺ channel, thus, increasing intracellular Ca²⁺ concentrations.³⁰

Klimontov et al⁴⁰ reported that the serum concentrations of Adipsin were increased in patients with T2DM by which they did not confirm the inverse relationship of Adipsin with T2DM. The possible reasons for these inconsistencies could be that the authors used small sample size of patients, a large number of patients receiving insulin therapy, and unable to differentiate subcutaneous and visceral fat depots as stated in their paper as a limitation of their study.

Conclusion and Future Perspective

Though there are different diagnostic and management modalities for DM, it is becoming a public health threat causing different micro and macro-complications in the world. To prevent these complications and to reduce mortality associated with DM, searching new promising diagnostic and therapeutic options are important. Adipsin, secreted by the adipocytes, has a crucial role in maintaining adipose tissue homeostasis and increases insulin secretion in response to glucose. It has the potential to become an early novel biomarker in patients with T2DM.

Various clinical and animal studies showed that there is a reduction in the plasma concentrations of Adipsin in animals/humans with DM. Additionally, Adipsin has varieties of effects in the pancreas including preserving β-cell mass by improving β-cell survival and maintaining β-cell transcriptional identity, and promoting insulin secretion from the β-cells of the pancreas. It also stimulates glucose transport for triglyceride accumulation in adipose tissue and inhibits lipolysis.

Further detailed animal and human studies will be required to confirm Adipsin as a novel biomarker for T2DM. Additionally, further investigations are in need to decide the mechanism by which Adipsin increases insulin secretion from β-cells of the pancreas. Adipsin has a biological function in in vivo studies and could be considered as a therapeutic option in the future.