Sugar, Uric Acid, and the Etiology of Diabetes and Obesity

Richard J. Johnson; Takahiko Nakagawa; L. Gabriela Sanchez-Lozada; Mohamed Shafiu; Shikha Sundaram; Myphuong Le; Takuji Ishimoto; Yuri Y. Sautin; Miguel A. Lanaspa


Diabetes. 2013;62(10):3307-3315. 

In This Article

Fructose-Induced Hyperuricemia, Insulin Resistance, and Diabetes

The observation that inhibition of uric acid synthesis prevented metabolic syndrome and hepatic steatosis leads to the question of how uric acid might contribute to insulin resistance and diabetes.

Hepatic Effects. The observation that uric acid can induce mitochondrial oxidative stress and fatty liver may explain how fructose induces insulin resistance. Mitochondrial oxidative stress has a role in driving insulin resistance.[42] In turn, the development of fatty liver is also linked with insulin resistance.[43]

Effects in the White Adipose Tissue. Uric acid may also induce insulin resistance via effects on adipocytes. Uric acid is taken up in adipocytes by an organic anion transporter where it induces oxidative stress via activation of NADPH oxidase, generating oxidized lipids and inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1).[29,44] Adiponectin synthesis is also inhibited.[44] In the hyperuricemic Pound mouse, the inhibition of uric acid synthesis by allopurinol attenuates the local inflammatory response in the visceral fat, reduces the expression of inflammatory cytokines, and enhances circulating levels of adiponectin in association with an improvement in insulin resistance.[44] Likewise, the reduction of uric acid by either allopurinol or benzbromarone in the fructose-fed rat results in less insulin resistance and decreases the leptin overexpression that occurs in the visceral fat.[4,45]

Vascular Effects. Fructose may also induce insulin resistance via effects on the vasculature. One of the major effects of insulin is to stimulate the release of NO from endothelial cells, where it causes vasodilation that aids delivery of glucose to the skeletal muscle. Mice that cannot generate endothelial NO develop features of metabolic syndrome and insulin resistance.[46] In this regard, uric acid inhibits endothelial NO generation, including in response to insulin.[32] Uric acid reduces endothelial NO via several mechanisms, including blocking the uptake of the substrate, l-arginine,[47] stimulating the degradation of l-arginine by arginase,[48] and scavenging NO by uric acid or by uric acid–generated oxidants.[32,34,49] Hyperuricemic rats have impaired endothelial function and hypertension that can be reversed by lowering uric acid or treating with l-arginine or antioxidants.[50–52] Hyperuricemia is also associated with endothelial dysfunction in humans, and lowering uric acid with allopurinol improves endothelial dysfunction in asymptomatic hyperuricemia, congestive heart failure, diabetes, chronic kidney disease, obstructive sleep apnea, and with smoking (rev. in.[53])

Islet Cell Effects. Chronic administration of fructose or sucrose to animals not only causes insulin resistance but may also result in type 2 diabetes.[5,54] Histologically, the islets show hyalinosis and macrophage infiltration, similar to what is observed in humans with type 2 diabetes. The mechanism by which fructose induces these changes is not known because the islet does not express GLUT5, which is the primary fructose transporter. However, we reported an upregulation of the urate transporter URAT-1 in islet cells of sucrose-fed rats in association with increased expression of MCP-1.[5] Incubation of cultured insulin-secreting islet cells with uric acid also causes oxidative stress and synthesis of MCP-1.[5] Oxidative stress in islets is considered to have a major role in causing the islet dysfunction of type 2 diabetes.