Engineered mesoporous silica particles (MSP) are thermally and chemically stable porous materials composed of pure silica and have attracted attention for their potential biomedical applications. Oral intake of engineered MSP is shown to reduce body weight and adipose tissue in mice. Here, clinical data from a first-in-humans study in ten healthy individuals with obesity are reported, demonstrating a reduction in glycated hemoglobin (HbA1c) and low-density lipoprotein cholesterol, which are well-established metabolic and cardiovascular risk factors. In vitro investigations demonstrate sequestration of pancreatic alpha-amylase and lipase in an MSP pore-size dependent manner. Subsequent ex vivo experiments in conditions mimicking intestinal conditions and in vivo experiments in mice show a decrease in enzyme activity upon exposure to the engineered MSP, presumably by the same mechanism. Therefore, it is suggested that tailored MSP act by lowering the digestive enzyme availability in the small intestine, resulting in decreased digestion of macronutrient and leading to reduced caloric uptake. This novel MSP based mechanism-of-action, combined with its excellent safety in man, makes it a promising future agent for prevention and treatment of metabolic diseases.

Aims/hypothesis Chronic stimulation of beta(2)-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of beta(2)-adrenoceptors. In the current study we further explored the potential therapeutic relevance of beta(2)-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect.

Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen.

Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment,p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg(-1) day(-1)(40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%,p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%,p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 +/- 0.31%/min in comparison with 0.15 +/- 0.36%/min in control mice,p < 0.05) and drastically reduced hepatic steatosis (by 40%,p < 0.01) and glycogen (by 23%,p < 0.05).

Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and glycogen. We conclude that selective beta(2)-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans.