Obesity, metabolic syndrome, and asthma are all rapidly increasing globally. Substantial emerging evidence suggests that these three conditions are epidemiologically and mechanistically linked. Since the link between obesity and asthma appears to extend beyond mechanical pulmonary disadvantage, molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin signaling provide mechanistic insight into the clinical evidence for the links between obesity, metabolic syndrome, and airway diseases, setting the stage for novel therapeutic avenues targeting these conditions. 1. Introduction It is now well recognized that obesity and asthma are epidemiologically linked [1–4]. Such a relationship is also seen between asthma and other markers of the metabolic syndrome such as insulin resistance and hypertension that cannot be accounted for by increased body mass alone [4–7]. While both obesity and asthma are individually associated with an increased state of inflammation [8], interestingly, in obese asthmatics, there is a dissociation between cellular inflammation and severity of symptoms, especially in women [9, 10]. This discordance would suggest that while obesity-related systemic inflammation can certainly be one mechanism for increased asthma risk, there is a need to examine mechanisms independent of cellular inflammation that may play a role in asthma in the context of conditions such as obesity and metabolic syndrome. A number of cellular signaling and metabolism mechanisms could contribute to increased asthma risk in patients with obesity and/or metabolic syndrome. Considering the fact that altered glucose metabolism occurs in both cases, and hyperinsulinemia with reduced insulin sensitivity is involved, an obvious potential factor affecting the lung is insulin itself, particularly a direct effect on structural cells as well as immune cells in the airway. In a large Danish cohort, it was observed that insulin resistance (IR) was more strongly related to asthma risk than any of the anthropometric parameters [11]. While
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