Hyperuricemia is an independent predictor of impaired fasting glucose and type 2 diabetes, but whether it has a causal role in insulin resistance remains controversial. Here we tested the hypothesis that lowering uric acid in hyperuricemic nondiabetic subjects might improve insulin resistance.
Methods
Subjects with asymptomatic hyperuricemia (n = 73) were prospectively placed on allopurinol (n = 40) or control (n = 33) for 3 months. An additional control group consisted of 48 normouricemic subjects. Serum uric acid, fasting glucose, fasting insulin, HOMA-IR (homeostatic model assessment of insulin resistance), and high-sensitivity C-reactive protein were measured at baseline and at 3 months.
Results
Allopurinol-treated subjects showed a reduction in serum uric acid in association with improvement in fasting blood glucose, fasting insulin, and HOMA-IR index, as well as a reduction in serum high-sensitivity C-reactive protein. The number of subjects with impaired fasting glucose significantly decreased in the allopurinol group at 3 months compared with baseline (n = 8 [20%] vs n = 30 [75%], 3 months vs baseline, P < 0.001). In the hyperuricemic control group, only glucose decreased significantly and, in the normouricemic control, no end point changed.
Conclusions
Allopurinol lowers uric acid and improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia. Larger clinical trials are recommended to determine if lowering uric acid can help prevent type 2 diabetes.
HermanJB, GoldbourtU. Uric acid and diabetes: observations in a population study. Lancet. 1982; 2(8292): 240–243.
8.
FacchiniF, ChenYD, HollenbeckCB. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA. 1991; 266(21): 3008–3011.
9.
Quiñones GalvanA, NataliA, BaldiS. Effect of insulin on uric acid excretion in humans. Am J Physiol. 1995; 268(1 pt 1): E1–E5.
10.
JohnsonRJ, NakagawaT, Sanchez-LozadaLG. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013; 62(10): 3307–3315.
11.
LanaspaMA, CicerchiC, GarciaG. Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver. PLoS One. 2012; 7(11): e48801.
12.
LanaspaMA, Sanchez-LozadaLG, ChoiYJ. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J Biol Chem. 2012; 287(48): 40732–40744.
13.
CicerchiC, LiN, KratzerJ. Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. FASEBJ. 2014; 28(8):–.
14.
Roncal-JimenezCA, LanaspaMA, RivardCJ. Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake. Metabolism. 2011; 60(9): 1259–1270.
15.
NakagawaT, HuH, ZharikovS. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006; 290(3): F625–F631.
16.
BaldwinW, McRaeS, MarekG. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes. 2011; 60(4): 1258–1269.
17.
OginoK, KatoM, FuruseY. Uric acid–lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail. 2010; 3(1): 73–81.
18.
DoganA, YarliogluesM, KayaMG. Effect of long-term and high-dose allopurinol therapy on endothelial function in normotensive diabetic patients. Blood Press. 2011; 20(3): 182–187.
19.
Perez-PozoSE, ScholdJ, NakagawaT. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond). 2010; 34(3): 454–461.
20.
MatthewsDR, HoskerJP, RudenskiAS. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28(7): 412–419.
21.
JohnsonRJ, SautinYY, OliverWJ. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?J Comp Physiol B. 2009; 179(1): 67–76.
22.
JohnsonRJ, LanaspaMA, GaucherEA. Uric acid: a danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations. Semin Nephrol. 2011; 31(5): 394–399.
23.
ChoiYJ, ShinHS, ChoiHS. Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes. Lab Invest. 2014; 94(10): 1114–1125.
24.
MazzaliM, HughesJ, KimYG. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001; 38(5): 1101–1106.
25.
Sánchez-LozadaLG, TapiaE, SantamaríaJ. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int. 2005; 67(1): 237–247.
26.
SutinAR, CutlerRG, CamandolaS. Impulsivity is associated with uric acid: evidence from humans and mice. Biol Psychiatry. 2014; 75(1): 31–37.
27.
LanaspaMA, Sanchez-LozadaLG, CicerchiC. Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS One. 2012; 7(10): e47948.
28.
KangDH, ParkSK, LeeIK. Uric acid–induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005; 16(12): 3553–3562.
29.
Sánchez-LozadaLG, LanaspaMA, Cristóbal-GarcíaM. Uric acid–induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations. Nephron Exp Nephrol. 2012; 121(3–4): e71–e78.
30.
SautinYY, NakagawaT, ZharikovS. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007; 293(2): C584–C596.
31.
ZhangY, YamamotoT, HisatomeI. Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells. Mol Cell Endocrinol. 2013; 375(1–2): 89–96.
32.
KratzerJT, LanaspaMA, MurphyMN. Evolutionary history and metabolic insights of ancient mammalian uricases. Proc Natl Acad Sci U SA. 2014; 111(10): 3763–3768.
JohnsonRJ, AndrewsP. Fructose, uricase, and the Back-to-Africa Hypothesis. Evol Anthropol. 2010; 19: 250–257.
36.
JohnsonRJ, AndrewsP. The fat gene: a genetic mutation in prehistoric apes may underlie today's pandemic of obesity and diabetes. Sci Am. 2015 in press.
37.
TapiaE, CristóbalM, García-ArroyoFE. Synergistic effect of uricase blockade plus physiological amounts of fructose-glucose on glomerular hypertension and oxidative stress in rats. Am J Physiol Renal Physiol. 2013; 304(6): F727–F736.
38.
CicerchiC, LiN, KratzerJ. Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. FASEBJ. 2014; 28(8): 3339–3350.
39.
NeelJV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”?Am J Hum Genet. 1962; 14: 353–362.
40.
JohnsonRJ, Perez-PozoSE, SautinYY. Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes?Endocr Rev. 2009; 30(1): 96–116.
41.
JohnsonRJ, SegalMS, SautinY. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007; 86(4): 899–906.
42.
FeigDI, MaderoM, JalalDI. Uric acid and the origins of hypertension. J Pediatr. 2013; 162(5): 896–902.
