Hyperuricemia in Young Adults and Diabetes Risk
Hyperuricemia in Young Adults and Diabetes Risk
Obesity is a well-recognized marker and risk factor for type 2 diabetes, but a considerable proportion of individuals who develop diabetes are not obese, suggesting that in the absence of obesity, there are other independent risk factors. Our results suggest that elevated serum urate concentration may be one such risk factor.
To our knowledge, the present study is the longest prospective, observational analysis to have assessed the link between hyperuricemia and future diabetes and other diabetes-related outcomes in nondiabetic persons aged 18–30 years. This association was independent of obesity and other known risk factors, including age, gender, body mass index, diastolic blood pressure, smoking, fasting glucose concentration, family history of diabetes, and physical activity level. Relatively few studies have prospectively assessed the relation between serum urate level and diabetes in young adults. Results presented here are in agreement with those of previously published studies performed in older subjects. Data from the Rotterdam Study showed that the age- and gender-adjusted hazard ratio for diabetes was greatest among persons in the highest quartile of serum urate level and the population attributable risk of hyperuricemia for diabetes was 24%. Herman and Goldbourt demonstrated that serum urate levels were higher in prediabetic subjects than in nondiabetics. In contrast, the present study assessed the association between serum urate level and both the incidence of type 2 diabetes and prediabetes endpoints and suggested that hyperuricemia can be a useful predictor of diabetes mellitus.
Pathophysiologic links between hyperuricemia, insulin resistance, and prediabetes have not been clearly established and are under investigation. Hyperuricemia is often the result of the underexcretion of urate, and renal clearance of urate has been shown to be inversely related to the degree of insulin resistance. In addition, insulin resistance is associated with reduced levels of nitric oxide, and increased serum urate concentration has been shown to reduce nitric oxide levels. Increases in the concentration of insulin may also affect renal tubular function and subsequent clearance of urate. This raises the possibility that hyperuricemia may merely be a marker for the renal effect of hyperinsulinemia. Our analyses showed a negligible relation between plasma insulin and serum urate levels at baseline, suggesting that hyperuricemia precedes insulin resistance, not vice versa.
Beyond this, there is some suggestion that the link between hyperuricemia and diabetes lies with the SCL2A9 gene and perhaps other genes not yet identified. SCL2A9 was first recognized to encode for the glucose/fructose transporter, GLUT9, which is expressed in 2 different isoforms in the liver, kidney, intestine, leukocytes, and chondrocytes. SCL2A9/GLUT9 was later identified in genome-wide studies as a major transporter of urate in the renal proximal tubule. Certain SCL2A9 alleles have been shown to be strongly associated with an increased risk of hyperuricemia and gout in different populations. When Brandstätter et al. analyzed 4 such alleles, 3 were shown to be significantly influenced by increasing body mass index. However, although the authors observed significant correlations between serum urate and the components of metabolic syndrome, no association between the 4 alleles and prevalent or incident metabolic syndrome could be established. Additional studies will be needed to determine whether the underlying genetic risks for hyperuricemia are also those for diabetes.
One possible limitation of this study is the type of population enrolled. It may be that persons who agree to participate in long-term studies such as the CARDIA Study are not representative of the general US population. As such, the "effect size" of the hyperuricemia-diabetes link in this cohort may not necessarily be generalizable to other populations. Future modeling studies can help establish the incremental value of adding serum urate level to the existing risk scoring methods. Another methodological limitation is that the pathway from normoglycemia through insulin resistance and prediabetes to diabetes could not be adequately modeled using our data. The main strengths of this study included the large number of participants, the long-term follow-up, and the young age of this biracial cohort. However, being an epidemiologic study, it did not address the pathophysiologic and mechanistic links underpinning our observations.
In summary, this study supports the use of serum urate concentration as an inexpensive marker for assessing the risk of future incident type 2 diabetes and diabetes-related outcomes in nonobese individuals. Serum urate level could be utilized either singly or as an integrated part of a risk score so that appropriate, targeted interventions could be formulated for at-risk patients.
Discussion
Obesity is a well-recognized marker and risk factor for type 2 diabetes, but a considerable proportion of individuals who develop diabetes are not obese, suggesting that in the absence of obesity, there are other independent risk factors. Our results suggest that elevated serum urate concentration may be one such risk factor.
To our knowledge, the present study is the longest prospective, observational analysis to have assessed the link between hyperuricemia and future diabetes and other diabetes-related outcomes in nondiabetic persons aged 18–30 years. This association was independent of obesity and other known risk factors, including age, gender, body mass index, diastolic blood pressure, smoking, fasting glucose concentration, family history of diabetes, and physical activity level. Relatively few studies have prospectively assessed the relation between serum urate level and diabetes in young adults. Results presented here are in agreement with those of previously published studies performed in older subjects. Data from the Rotterdam Study showed that the age- and gender-adjusted hazard ratio for diabetes was greatest among persons in the highest quartile of serum urate level and the population attributable risk of hyperuricemia for diabetes was 24%. Herman and Goldbourt demonstrated that serum urate levels were higher in prediabetic subjects than in nondiabetics. In contrast, the present study assessed the association between serum urate level and both the incidence of type 2 diabetes and prediabetes endpoints and suggested that hyperuricemia can be a useful predictor of diabetes mellitus.
Pathophysiologic links between hyperuricemia, insulin resistance, and prediabetes have not been clearly established and are under investigation. Hyperuricemia is often the result of the underexcretion of urate, and renal clearance of urate has been shown to be inversely related to the degree of insulin resistance. In addition, insulin resistance is associated with reduced levels of nitric oxide, and increased serum urate concentration has been shown to reduce nitric oxide levels. Increases in the concentration of insulin may also affect renal tubular function and subsequent clearance of urate. This raises the possibility that hyperuricemia may merely be a marker for the renal effect of hyperinsulinemia. Our analyses showed a negligible relation between plasma insulin and serum urate levels at baseline, suggesting that hyperuricemia precedes insulin resistance, not vice versa.
Beyond this, there is some suggestion that the link between hyperuricemia and diabetes lies with the SCL2A9 gene and perhaps other genes not yet identified. SCL2A9 was first recognized to encode for the glucose/fructose transporter, GLUT9, which is expressed in 2 different isoforms in the liver, kidney, intestine, leukocytes, and chondrocytes. SCL2A9/GLUT9 was later identified in genome-wide studies as a major transporter of urate in the renal proximal tubule. Certain SCL2A9 alleles have been shown to be strongly associated with an increased risk of hyperuricemia and gout in different populations. When Brandstätter et al. analyzed 4 such alleles, 3 were shown to be significantly influenced by increasing body mass index. However, although the authors observed significant correlations between serum urate and the components of metabolic syndrome, no association between the 4 alleles and prevalent or incident metabolic syndrome could be established. Additional studies will be needed to determine whether the underlying genetic risks for hyperuricemia are also those for diabetes.
One possible limitation of this study is the type of population enrolled. It may be that persons who agree to participate in long-term studies such as the CARDIA Study are not representative of the general US population. As such, the "effect size" of the hyperuricemia-diabetes link in this cohort may not necessarily be generalizable to other populations. Future modeling studies can help establish the incremental value of adding serum urate level to the existing risk scoring methods. Another methodological limitation is that the pathway from normoglycemia through insulin resistance and prediabetes to diabetes could not be adequately modeled using our data. The main strengths of this study included the large number of participants, the long-term follow-up, and the young age of this biracial cohort. However, being an epidemiologic study, it did not address the pathophysiologic and mechanistic links underpinning our observations.
In summary, this study supports the use of serum urate concentration as an inexpensive marker for assessing the risk of future incident type 2 diabetes and diabetes-related outcomes in nonobese individuals. Serum urate level could be utilized either singly or as an integrated part of a risk score so that appropriate, targeted interventions could be formulated for at-risk patients.
