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Tissue Renin-Angiotensin systems: a unifying hypothesis of metabolic disease
Jeppe Skov1, Frederik Persson2, Jørgen Frøkiær3
1Department of Endocrinology and Internal Medicine, Aarhus University Hospital , Aarhus , Denmark ; Novo Nordisk A/S , Bagsvaerd , Denmark.
Abstract:
The actions of angiotensin peptides are diverse and locally acting tissue renin-angiotensin systems (RAS) are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g., diabetes) and its complications and blockers of RAS have been demonstrated to prevent diabetes in humans. Hyperglycemia, obesity, hypertension, and cortisol are well-known risk factors of metabolic disease and all stimulate tissue RAS whereas glucagon-like peptide-1, vitamin D, and aerobic exercise are inhibitors of tissue RAS and to some extent can prevent metabolic disease. Furthermore, an activated tissue RAS deteriorates the same risk factors creating a system with several positive feedback pathways. The primary effector hormone of the RAS, angiotensin II, stimulates reactive oxygen species, induces tissue damage, and can be associated to most diabetic complications. Based on these observations, we hypothesize that an activated tissue RAS is the principle cause of metabolic syndrome and type 2 diabetes, and additionally is mediating the majority of the metabolic complications. The involvement of positive feedback pathways may create a self-reinforcing state and explain why metabolic disease initiate and progress. The hypothesis plausibly unifies the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control.
Insights
Tissue renin-angiotensin system (RAS) activation drives metabolic syndrome and type 2 diabetes. Inhibiting this system may prevent and treat these conditions and their complications.
Area of Science:
- Endocrinology
- Metabolic Disease Research
- Cardiovascular Physiology
Background:
- Tissue renin-angiotensin systems (RAS) are widespread and linked to metabolic disease.
- Risk factors like hyperglycemia and obesity activate tissue RAS, while certain factors inhibit it.
- Activated RAS exacerbates metabolic risk factors, creating detrimental feedback loops.
Purpose of the Study:
- To hypothesize that activated tissue RAS is the primary cause of metabolic syndrome and type 2 diabetes.
- To propose that tissue RAS mediates most metabolic complications.
- To suggest tissue RAS regulation is central to metabolic control.
Main Methods:
- Review of existing literature on tissue RAS, metabolic disease, and related risk factors.
- Analysis of the role of angiotensin II and feedback pathways in metabolic dysfunction.
- Formulation of a unifying hypothesis based on observed correlations and mechanisms.
Main Results:
- Activated tissue RAS correlates strongly with metabolic disease and its complications.
- Key risk factors (hyperglycemia, obesity, hypertension, cortisol) stimulate tissue RAS.
- Inhibitors of tissue RAS (GLP-1, vitamin D, exercise) show potential in preventing metabolic disease.
Conclusions:
- An activated tissue RAS is hypothesized as the principal driver of metabolic syndrome and type 2 diabetes.
- Positive feedback loops within the tissue RAS may explain disease initiation and progression.
- This hypothesis unifies major metabolic disease predictors and highlights tissue RAS as a central regulatory point.
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