TXNIP Regulates Peripheral Glucose Metabolism in Humans

Abstract

Background

Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure.

Methods and Findings

We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM.

Conclusions

TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic β-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.

Abstract

Vamsi Mootha, Leif Groop, and colleagues report that TXNIP regulates insulin-dependent and -independent pathways of glucose uptake in human skeletal muscle and that its expression is elevated in individuals with prediabetes and type 2 diabetes.

Editors' Summary

Background.

An epidemic of diabetes mellitus is threatening world health. 246 million people (6% of the world's population) already have diabetes and it is estimated that within 20 years, 380 million people will have this chronic disease, most of them in developing countries. Diabetes is characterized by high blood sugar (glucose) levels. It arises when the pancreas does not make enough insulin (type 1 diabetes) or when the body responds poorly to insulin (type 2 diabetes). Insulin, which is released in response to high blood glucose levels, instructs muscle, fat, and liver cells to take glucose (a product of food digestion) out of the bloodstream; cells use glucose as a fuel. Type 2 diabetes, which accounts for 90% of all cases of diabetes, is characterized by impaired glucose uptake by target tissues in response to insulin (this “insulin resistance” is one of the first signs of type 2 diabetes) and inappropriate glucose release from liver cells. Over time, the pancreas may also make less insulin. These changes result in poor glucose homeostasis (inadequate control of blood sugar levels), which can cause life-threatening complications such as kidney failure and heart attacks.

Why Was This Study Done?

If the world diabetes epidemic is to be halted, researchers need a better understanding of glucose homeostasis and need to identify which parts of this complex control system go awry in type 2 diabetes. This information might suggest ways to prevent type 2 diabetes developing in the first place and might reveal targets for drugs that could slow or reverse the disease process. In this study, the researchers have used multiple approaches to identify a new mediator of glucose homeostasis and to investigate whether this mediator is causally involved in the development of type 2 diabetes.

What Did the Researchers Do and Find?

The researchers took small muscle samples from people who did not have diabetes before and after increasing their blood insulin levels and used a technique called “microarray expression profiling” to identify genes whose expression was induced or suppressed by insulin. One of the latter genes was thioredoxin interacting protein (TXNIP), a gene whose expression is strongly induced by glucose yet suppressed by insulin. They next used previously published microarray expression data to show that TXNIP expression was consistently higher in the muscles of patients with diabetes or prediabetes (a condition in which blood glucose levels are slightly raised) than in normal individuals. The researchers then examined whether TXNIP expression was correlated with glucose uptake, again using previously published data. In people with no diabetes and those with prediabetes, as glucose uptake rates increased, TXNIP expression decreased but this inverse correlation was missing in people with diabetes. Finally, by manipulating TXNIP expression levels in insulin-responsive cells grown in the laboratory, the researchers found that TXNIP overexpression reduced basal and insulin-stimulated glucose uptake but that reduced TXNIP expression had the opposite effect.

What Do These Findings Mean?

These results provide strong evidence that TXNIP is a regulator of glucose homeostasis in people. Specifically, the researchers propose that TXNIP regulates glucose uptake in the periphery of the human body by acting as a glucose- and insulin-sensitive switch. They also suggest how it might be involved in the development of type 2 diabetes. Early in the disease process, a small insulin deficiency or slightly raised blood sugar levels would increase TXNIP expression in muscles and suppress glucose uptake by these cells. Initially, the pancreas would compensate for this by producing more insulin, but this compensation would eventually fail, allowing blood sugar levels to rise sufficiently to increase TXNIP expression in the pancreas. Previously published results suggest that this would induce the loss of insulin-producing cells in the pancreas, thus further reducing insulin production and glucose uptake in the periphery and, ultimately, resulting in type 2 diabetes. Although there are many unanswered questions about the exact role of TXNIP in glucose homeostasis, these results help to explain many of the changes in glucose control that occur early in the development of diabetes. Furthermore, they suggest that interventions designed to modulate the activity of TXNIP might break the vicious cycle that eventually leads to type 2 diabetes.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040158.

• The MedlinePlus encyclopedia has pages on diabetes

• The US National Institute of Diabetes and Digestive and Kidney Diseases has information for patients on diabetes

• Information on diabetes is available for patients and professionals from the US Centers for Disease Control and Prevention

• The American Diabetes Association provides information on diabetes for patients

• International Diabetes Federation has information on diabetes and a recent press release on the global diabetes epidemic