Pleiotropic Effects of Totum-63—Simultaneous Targeting of Multiple Diabetes Mediators

In 2015, 30.3 million Americans had diabetes, and 84.1 million Americans had prediabetes. Up to 70% of individuals with prediabetes will eventually develop type 2 diabetes (T2D). Additional intervention strategies are needed to manage prediabetes. The pathophysiology of T2D is complex and characterized by alterations in many tissues. We have previously shown that Totum-63 is effective to prevent glucose homeostasis impairments in rodent models of T2D. In an open phase I/II clinical study, Totum-63 also improved glucose and insulin responses to a standardized breakfast in healthy subjects. In order to better understand the mechanisms involved in the beneficial effects of Totum-63, we have conducted early interventions with oral administration of Totum-63 in high fat-fed mice and in db/db mice. Body weight gain and fat mass accumulation, known as early mediators of insulin-sensitivity defectiveness, were markedly lowered. Liver and skeletal muscle insulin signaling pathways were activated in a similar fashion despite lower circulating insulin levels, suggesting an improvement in insulin sensitivity. Hepatic triglyceride content, known as a powerful inductor of liver insulin resistance, was reduced. Totum-63 administration increased liver gene expression of FGF-21, which has been involved in the regulation of many metabolic pathways. In db/db mice, Totum-63 administration delayed the defect of insulin secretion, suggesting a protective role on pancreatic beta-cells. Finally, Totum-63 also showed preventive effects on high fat diet-induced gut microbiota dysbiosis, that has been postulated as a key driver of many metabolic disturbances.

In conclusion, Totum-63 displays pleiotropic beneficial effects on tissues known as major contributors to T2D development. Totum-63 is a promising intervention strategy to prevent T2D development, and is currently under investigation in phase II clinical trial.