Targeting the root cause of obesity-related comorbidities through weight independent and dependent actions on insulin sensitivity: Benefits of dual amylin and calcitonin receptor agonists

Insulin is the major endocrine hormone responsible for regulating whole-body glucose homeostasis by regulating glucose uptake in insulin-sensitive tissue. Obesity is one of the main factors initiating the development of insulin resistance through increased adipose tissue size, inflammation, and ectopic fat deposition in insulin-sensitive tissues. Inflammation and fat accumulation are key drivers for losing insulin sensitivity and are thereby part of triggering a wide range of pathological conditions and obesity-related comorbidities, in which insulin resistance is central. These included diabetes, liver and cardiovascular complications, musculoskeletal conditions, and neurodegenerative disorders among others. The number of conditions derived from metabolic dysregulation originating from insulin resistance highlights the importance of treating insulin resistance. The management of insulin resistance has evolved significantly with the ongoing growth of therapeutic options. The therapeutic landscape includes both potent weight loss therapies improving insulin sensitivity indirectly and insulin-sensitizing therapies specifically targeting insulin resistance. On the horizon are novel drug candidates like dual amylin and calcitonin receptor agonists (DACRAs), which elicit weight-loss, but also have insulin-sensitizing properties through a weight-independent action, thereby providing highly relevant additional value to the existing therapeutic options. This review introduces the mechanisms behind insulin resistance, focusing on the key insulin target tissues; skeletal muscle, liver, and white adipose tissue. More importantly, diseases triggered by insulin resistance are described, followed by a highlight of treatments improving insulin sensitivity through different mechanisms of action.