Glycerate from Fat-modulating Fructose Metabolism as a Mediator of Diabetes

The prevalence of diabetes is on the rise, thus imposing a huge burden on our society. In addition to genetic and environmental risk factors, obesity strongly predicts the development of diabetes. Owing to the strong correlation between saturated fat and fructose intake and the incidence of metabolic diseases and obesity, dietary intervention is one of the common management strategies to control obesity and diabetes. Although there are still contentious debates on whether a low-fat or low-carbohydrate diet is beneficial to metabolic health, less is known about the interaction between lipid and carbohydrate metabolism. One of the overlooked interactions is how fat intake modulates fructose metabolism.

The effects of high-fat intake were first studied in mouse models. Coupled with fructose stable isotopic tracing, we profiled the fructose metabolism in various tissues among mice fed with either a high-fat diet or a control diet. We also surveyed the fructose-derived metabolites in the circulation to establish the systematic perturbations of fructose metabolism by the high-fat diet. We unveiled that a high-fat diet potentiates intestinal fructose metabolism and the production of glycerate. The fructose-derived glycerate then enters the circulation and reaches the pancreas.

We performed daily glycerate administration to model the high circulating glycerate level among mice. Through metabolic profiling, we found that high circulating glycerate can cause glucose intolerance but not induce insulin resistance. The observed glucose intolerance phenotype is likely related to the reduction in circulating insulin levels and that reduced insulin secretion is independent of the insulin sensitivity among the mice treated with glycerate. In the investigation of the pancreatic islets, we found glycerate treatment promotes pancreatic beta-cell damage and apoptosis.

In conclusion, we demonstrated the interaction between fat and fructose intake, in which high fat intake enhances the fructose metabolism in the small intestine. The up-regulated fructose metabolism in the small intestine enhances the production of glycerate. High circulating glycerate is a risk factor for diabetes development via depletion of insulin content in pancreatic islets. Therefore, this study discovers a novel mechanism for fructose-induced diabetes via the action of glycerate. It also supports the idea of reducing fat and fructose intake simultaneously, rather than either macronutrient alone, to achieve maximal metabolic health benefits.