Is Insulin Resistance an Adaptive Response? Clues from Nature

Insulin is an evolutionarily conserved peptide hormone best known for regulating glucose homeostasis, yet its physiological roles extend well beyond glucose regulation. Across the animal kingdom, insulin signaling influences such diverse physiological processes as growth and development, stress responses, cognition, learning, memory formation, sodium balance, thermoregulation, reproduction, and vision. Although traditional laboratory models have advanced our understanding of insulin signaling and diabetes pathophysiology, they represent a relatively narrow perspective on the diversity of glucose regulation strategies and roles of insulin observed in the animal kingdom. Examination of insulin resistance through a comparative physiology lens provides a broader evolutionary framework for understanding how insulin signaling pathways and nutrient regulation have been conserved or modified across species in response to various environmental pressures. Evidence from this approach demonstrates diverse glucose regulation strategies noting that insulin resistance can at times function as an adaptive response to various stressors, even in humans. Several recent reviews have explored the evolution of insulin resistance and adaptive insulin resistance, although most have focused on a limited subset of vertebrates. Therefore, the intent of the present review is not to reproduce these efforts but to synthesize evidence across taxa, highlighting the diversity of strategies for glucose regulation and adaptive insulin resistance in vertebrates through the lens of comparative physiology. By examining insulin signaling within an evolutionary context, this review aims to identify unifying principles that challenge conventional paradigms of insulin resistance as solely pathological and instead position it as a context-dependent physiological adaptation across species.