Diabetes mellitus is a multisystemic endocrine disorder known to interfere with the regulation of major metabolic pathways irrespective of its etiology with the common pathology of chronic hyperglycemia. Diabetes and its secondary complications are clinically treated with several drugs having the different mechanism of actions, such as biguanides, sulphonylureas, meglitinides, thiazolidines, α-glucosidase inhibitors, bile acid sequestrants, SGLT-2 (sodium/glucose cotransporter 2) inhibitors, GLP-1 (glucagon-like peptide-1) receptor agonists and insulin, either as monotherapy or combinatorial strategy. However, the maintenance of normoglycemia remains a major task in the treatment of patients with type 2 diabetes mellitus (T2DM) [1]. Accordingly, instead of a one-size-fit all approach, personalization is necessary, balancing the benefit of glycemic control with its potential risk factors taking into consideration of various etiological factors such as the patient's age, blood pressure control, lipid management, comorbidities that are frequently encountered in diabetic patients.

The ecologically derived plant secondary metabolites are known to play a pivotal role in alleviating the primary and secondary complications of dreadful human diseases such as cancer, diabetes, and atherosclerosis [2]. Among the various phytoingredients, flavonoids are known for their wide range of pharmacological as well as beneficial effects in the maintenance of human health care especially in quenching oxidative stress, a contributory factor for the progression of several secondary complications [3].

Metformin remains the optimum drug for the treatment of T2DM due to its proven safety record, weight neutrality and possible benefits on cardiovascular outcomes in addition to its low cost. Although metformin is efficacious in lowering the blood glucose levels, many patients with T2DM are not adequately controlled when metformin is prescribed as a monotherapy [4]. In the 21st century, a new class of metallopharmaceutical compounds containing zinc ions is expected to treat both the types of diabetes mellitus by making use of its unique pharmacological properties [5]. Ever since in 1980, Coulston and Dandona [6] reported the insulin mimetic activity of zinc ions, several researchers develop zinc complexes with various coordination modes around zinc (II) ion and evaluated its glucose normalizing effect. In the recent past, we have synthesized several new zinc complexes [78910] and evaluated for their toxicity as well as pharmacological properties in high fat diet (HFD) fed-low dose streptozotocin (STZ) induced experimental T2DM in rats. More recently, we have synthesized a metformin-3-hydroxyflavone complex and evaluated its antidiabetic efficacy [1112]. In the light of knowledge and expertise gained, in the present study an attempt has been made to synthesize a new metformin-zinc-flavonol complex and biochemically evaluated its toxicity as well as antidiabetic properties.

The effect of oral administration of the zinc-mixed ligand, Schiff base complex and metformin on glucose tolerance in diabetic rats after oral glucose load is represented in Table 1. Although the blood glucose levels reached a maximum peak value at 60 minutes after oral glucose load in all the three experimental groups of rats, the levels were significantly lower than those observed in diabetic group of rats and the peak was reversed to the physiological level in the next 60 minutes. However, the diabetic rats treated with zinc-mixed ligand complex showed statistically significant improvement in glucose homeostasis when compared to other two experimental groups of rats. Accordingly, the altered values of HOMA-IR and QUICK-I observed in the diabetic group of rats (7.80±0.06 and 0.30±0.01, respectively) were brought back to near normal values (4.01±0.04 and 0.38±0.01, respectively) upon treatment with oral administration of mixed ligand zinc complex.

Table 2 depicts the levels of fasting blood glucose, hemoglobin, glycosylated hemoglobin, plasma insulin, C-peptide, plasma protein, urea, uric acid, and creatinine in control as well as experimental groups of rats. The fasting blood glucose levels were elevated in the experimental diabetic rats which ultimately leads to elevated glycosylated hemoglobin levels. Plasma insulin and C-peptide levels in the diabetic rats were markedly reduced when compared with control rats whereas these altered levels were significantly improved to physiological range in diabetic rats treated with Schiff base as well as mixed ligand zinc complex. Urine sugar which was present in diabetic rats was no longer detected in the treated groups of rats.

The synthesis of a Schiff base ligand (L) from the co-ordination between 3-hydroxyflavone and metformin by a molar ratio method was yellow in color. Similarly, the new zinc-mixed ligand complex synthesized using Schiff base ligand (L) and zinc acetate was pale yellow in color and the yield was about 96%. The molecular formula of the proposed zinc-mixed ligand complex is C₃₈H₃₅N₁₀O₄ Zn. The IR, Mass spectra, ¹H NMR, and ¹³C NMR spectral data provide a substantial evidence for the synthesis of the zinc-mixed ligand complex.

The data obtained through the oral glucose tolerance test evidenced the better efficacy of the zinc-mixed ligand complex than the metformin-3-hydroxyflavone complex in maintaining normoglycemia. The observed increase in the levels of fasting blood glucose and HbA1c is attributed to the insulin insufficiency and/or insulin resistance in diabetic rats. The normalization of altered biochemical parameters suggest that the zinc complex improves glucose homeostasis in diabetic rats and the efficacy was found to be superior to the Schiff base treated group of rats and the same was comparable with metformin which was administered at a concentration of 50 mg/kg body weight.

Enhanced insulin resistance coupled with increased muscle wasting is responsible for the observed decrease in protein synthesis which resulted in decreased plasma protein level in diabetic condition [15]. Muscle wasting due to chronic hyperglycemia leads to prominent scarcity of both hepatic as well as plasma proteins which in turn results in the excessive accumulation of nitrogenous wastes such as urea, uric acid, and creatinine in the systemic circulation than its excretion. The administration of zinc-mixed ligand complex to diabetic rats normalized the levels of plasma protein, blood urea, uric acid, and creatinine indicating the recovered renal function due to improved glycemic control [16].

The data obtained through OGTT, HOMA-IR, QUICK-I, and biochemical parameters evidenced that the oral administration of zinc-mixed ligand complex significantly improves the insulin sensitivity in diabetic rats to maintain normoglycemia. Normalization of protein metabolism upon treatment with zinc-mixed ligand complex suggests that the complex exerts beneficial effects on renal functions. In summary, the results of the present study clearly established that the zinc-mixed ligand complex shows better antidiabetic properties relatively at a lesser concentration than the Schiff base indicating that the addition of zinc significantly improved the efficacy of metformin-3-hydroxyflavone. Further studies are in progress to understand the molecular mechanisms involved in the action of zinc-mixed ligand complex in ameliorating the primary and secondary complications of T2DM.