Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists (vol 13, 942, 2022)

Abstract Since its debut a century ago, insulin therapies have saved many lives and are now routinely used by patients with diabetes to manage hyperglycemia. Exemplary early studies of insulin molecular pathways led to the realization of the critical roles of signaling transduction in mediating its pleiotropic actions. Multiple insulin analogs have been developed in the last few decades primarily focused on improving the time action profile without affecting ligand-receptor interaction or functional selectivity in downstream signaling. As a result, inherent liabilities of injectable insulins continue to limit insulin’s true therapeutic potential. For example, fear of hypoglycemia often leads to underdosing and inadequate glycemic control and, as a consequence, continued risk of diabetic complications. Efforts to develop hepatic targeted basal insulin analogs lead to reduced effect on skeletal muscle and lower hypoglycemic risk but failed to adequately suppress lipolysis. To achieve both functional selectivity and a more desirable pharmacological profile, we evaluated a series of covalent insulin dimers that act in cellular assays as insulin receptor partial agonists (IRPA). Structural studies revealed distinct insulin receptor interactions compared to insulin analogs. Furthermore, IRPAs were shown to induce biased signaling in cellular assays that supports the potential for reduced mitogenic and atherosclerotic activities compared to regular insulin. In vivo, IRPAs exhibit tissue preferential action that attenuates stimulation of skeletal muscle glucose uptake while retaining hepatic and adipose actions to regulate glucose production and lipolysis, respectively. These attributes are expected to significantly reduce the hypoglycemic risk while achieving similar glycemic control and less body weight gain relative to comparator insulin analogs in animal models. Furthermore, IRPA lessens receptor internalization resulting in a slower clearance and long duration of action across species, an optimal feature for a basal insulin. In summary, IRPA possesses the desired molecular features that are required to reduce the hypoglycemic risk while maintaining the broad metabolic benefits of insulin therapy and as such represents a potential transformative therapy for patients with diabetes.