Hyperuricemia in type 2 diabetic model KK-Ay/Ta mice: a potent animal model with positive correlation between insulin resistance and plasma high uric acid levels

Abstract

ObjectiveHyperuricemia is recognized as a main cause of gout. Accumulating clinical evidence suggests that hyperuricemia is strongly associated with insulin resistance and abnormal glucose metabolism. However, there seem no proper animal models for investigating such associations. Ideal animal model is considered to be hyperuricemic as well as diabetic. Selecting the KK-Ay/Ta mouse model, the relationship between hyperuricemia and insulin resistance has been studied to characterize such an animal model.ResultsMale type 2 diabetic KK-Ay/Ta and age-matched normal C57BL/6J mice were maintained on a basal 20% casein diet for 35 days. Food intake, body weight gain, levels of plasma uric acid, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride in KK-Ay/Ta mice were significantly higher than those in normal mice. Plasma uric acid levels showed significant positive correlations with plasma glucose, insulin, HOMA-IR and triglyceride levels. These results suggest that the KK-Ay/Ta mouse strain is useful for studies on correlation between hyperuricemia and insulin resistance, and for those on effects of foods and their components on the relations.

Antidiabetic Effect of Taxifolin in Cultured L6 Myotubes and Type 2 Diabetic Model KK-Ay/Ta Mice with Hyperglycemia and Hyperuricemia

“…Plasma triglyceride and total cholesterol levels were significantly elevated in the diabetic state (CNT) compared with those in the normal state (NOR), but these elevations were not significantly suppressed (p < 0.1) by oral administration of taxifolin (TXF) (Figure 5A,B). The plasma uric acid level was significantly higher in the diabetic state (CNT) than in the normal state (NOR), confirming the occurrence of hyperuricemia in T2D model KK-A y /Ta mice as previously reported [19], and TXF was found to significantly suppress this hyperuricemia (Figure 5C) as well as hyperglycemia (Figure 4B). In contrast, adiponectin, which is known to activate muscle AMPK [27], significantly decreased in T2D model KK-A y /Ta mice (CNT) in comparison with normal ones (NOR), and TXF administration exerted no influence on this reduction (TXF) (Figure 5D).…”

“…Plasma triglyceride and total cholesterol levels were si icantly elevated in the diabetic state (CNT) compared with those in the normal (NOR), but these elevations were not significantly suppressed (p < 0.1) by oral admini tion of taxifolin (TXF)(Figure 5A,B). The plasma uric acid level was significantly high the diabetic state (CNT) than in the normal state (NOR), confirming the occurrenc hyperuricemia in T2D model KK-A y /Ta mice as previously reported [19], and TXF Figure 5 shows the effect of taxifolin on the plasma levels of triglyceride (A), total cholesterol (B), uric acid (C), and adiponectin (D) 6 h after fasting at the end of the experimental period of four weeks. Plasma triglyceride and total cholesterol levels were significantly elevated in the diabetic state (CNT) compared with those in the normal state (NOR), but these elevations were not significantly suppressed (p < 0.1) by oral administration of taxifolin (TXF) (Figure 5A,B).…”

“…Adachi et al found that the levels of plasma uric acid, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride in KK-A y /Ta mice were significantly higher than those in normal mice. In addition, plasma uric acid levels showed significant and positive correlations with plasma glucose, insulin, HOMA-IR and triglyceride levels [19]. TXF has been demonstrated to suppress UA production in AML12 hepatocytes and purine body-induced hyperuricemia in mice [20].…”

Hyperuricemia and gout caused by missense mutation in d-lactate dehydrogenase

“…Although it is possible that hyperuricemia might be causative of diabetes rather than the other way around (31), the causality remains uncertain, because confounders, reverse causality, or common etiological factors might explain the epidemiological results (29). In fact, recent human and mouse data imply that diabetes increases the risk of hyperuricemia (29,32). Notably, significantly (on average >10-fold) elevated levels of d-lactate .…”

A Head-To-Head Comparison of Benzbromarone and Allopurinol on the Risk of Type 2 Diabetes Mellitus in People With Asymptomatic Hyperuricemia

“…Many studies have demonstrated a positive correlation of hyperuricemia with the risk ofT2DM. Moreover, one animal-model research has shown that the serum level of uric acid could be positively associated with insulin resistance in mice ( Adachi et al, 2017 ). An observational study showed that after adjusting for diabetic risk factors, people with a higher level of serum uric acid might have a greater risk of developing T2DM as compared to people with lower serum level of uric acid ( Sluijs et al, 2013 ).…”