The hormone triggers insulin resistance in blood vessel endothelium in obesity
A large proportion of the approximately six million patients in Germany suffering from type 2 diabetes are overweight. The effect of insulin is impaired in these patients. The cause of this insulin resistance has been sought primarily in metabolically active organs for a long time. Researchers at the Max Planck Institute for Heart and Lung Research in Bad Nauheim have now shown that the effects of insulin on the innermost cell layer of blood vessels, the endothelium, are of great importance for insulin resistance in fat tissue and muscle. The key molecule here is the hormone adrenomedullin. With this study, the researchers hope to have found the basis for a new therapeutic principle for type 2 diabetes. The goal is now to develop substances that specifically target blood vessels.
In around 90 percent of type 2 diabetes patients, the cause is severe overweight, also known as obesity.
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In nine out of ten patients with type 2 diabetes, severe obesity, known as adiposity, leads to diabetes. Type 2 diabetes is characterized by the fact that body cells no longer take up sufficient glucose. As a result, the glucose level in the blood rises. In this process, insulin loses its effect at least in part, and we speak of insulin resistance.
To clarify the cause of insulin resistance in adipose patients, research has focused primarily on metabolic organs such as the liver, fat tissue, and skeletal muscle. In the cells of these organs, there are receptors for insulin. However, no therapeutic approaches have yet been developed to overcome insulin resistance. Researchers from the Department of Pharmacology at the Max Planck Institute for Heart and Lung Research in Bad Nauheim investigated the role of the innermost cell layer in blood vessels, the endothelium, in the development of type 2 diabetes in conjunction with obesity in a study.
Although it has been known that insulin receptors are also present on endothelial cells, their importance in the development of diabetes has been underestimated until now. “When insulin docks onto its receptor on the endothelium and activates it, this leads to an expansion of blood vessels and an improved permeability of the vascular wall for insulin. As a result, glucose and insulin can better enter the metabolic organs such as the liver and muscle,” explains Haaglim Cho, first author of the study.
The study conducted by the Bad Nauheimer researchers has now shown for the first time that this mechanism can be disturbed in the case of severe obesity. In mice that became obese through a particularly calorie-rich diet, insulin resistance developed after some time, Cho explains further. “We were able to identify a reduced activity of the insulin receptors on the endothelium as the cause.” The results suggest that insulin resistance in the endothelium leads to a reduced insulin effect in the entire organism, as the two mechanisms by which insulin enters the metabolic organs are then impaired.
But what is the cause of the development of insulin resistance on the endothelium? Further experiments led the researchers to adrenomedullin. This hormone is released from fat cells into the blood in particular in overweight individuals. “We found a comparable effect in obese mice, namely that the adrenomedullin level in the blood is significantly increased. Also, another protein, complement factor H, is elevated in the blood of both mice and humans with obesity. Our study showed that both factors enhance their effect on the insulin receptor,” explains Cho.
Adrenomedullin receptor inhibits insulin receptor
In healthy, normal-weight mice, insulin increases blood flow to the muscles by activating its receptor on the inside of the blood vessels (the endothelium) (shown in red, left). As a result, insulin and glucose reach the muscle cells efficiently, and insulin promotes the uptake of glucose into the muscle cells. This leads to a reduction in blood glucose levels. In overweight diabetic mice (middle pictures), there is considerable insulin resistance in the vascular system, which means that insulin has little effect on blood flow to the muscles. This insulin resistance in the vasculature is caused by increased levels of adrenomedullin. If the adrenomedullin receptor is switched off in overweight diabetic animals (right), adrenomedullin loses its effect and insulin resistance decreases significantly. Insulin can now, as in a healthy state, cause a significant increase in muscle perfusion, leading to an improved metabolic state with reduced blood glucose levels.
© MPI for Heart and Lung Research
The effect of increased concentrations of adrenomedullin and complement factor H on insulin activity was shown in animal studies on mice: Both factors activate the adrenomedullin receptor on the endothelium synergistically, i.e., they enhance each other’s effect. The activated adrenomedullin receptor, in turn, strongly inhibits the insulin receptor. As a result, the insulin effect is reduced. “We were able to confirm this finding in healthy, normal-weight mice to which we administered adrenomedullin. This also led to insulin resistance,” says Cho. Conversely, mice in which the production of adrenomedullin or the activation of the endothelial adrenomedullin receptor was temporarily blocked through genetic intervention showed a normal insulin metabolism, even when they were obese.
Stefan Offermanns, Director of the Department of Pharmacology, summarizes the study’s findings: “Our data show the insulin effects in blood vessels and how important the effect of insulin on blood vessels is for systemic insulin effects.” Above all, the study reveals a mechanism by which the systemic insulin resistance of a type 2 diabetes triggered by obesity is largely based on insulin resistance in the vascular system. “We hope that with the improved understanding of the type 2 diabetes caused by adiposity, a first step has been taken towards the development of new substances that can treat type 2 diabetes,” explains Offermanns.”
