Insulin resistance and type 2 diabetes as allostatic responses to chronic nutrient excess.

Abstract

Obesity-related type 2 diabetes (T2D) is currently defined by insulin resistance and impaired insulin secretion. Sulfonylureas, thiazolinediones, and insulin are effective at lowering glycemia yet have not consistently translated into improved long-term outcomes. In contrast, recent interventions often produce metabolic benefits that exceed expectations based on glucose lowering alone. These contrasting observations suggest that our understanding of T2D pathophysiology is incomplete. We propose that, in obesity-related prediabetes and early T2D, insulin resistance, attenuated glucose-stimulated insulin secretion, modest hyperglycemia, and glucosuria represent beneficial functional changes in response to nutrient excess. These allostatic adaptive responses limit glucose flux into metabolically vulnerable tissues and reduce nutrient stress (nutri-stress). From this perspective, T2D is not simply a failure of glucose regulation but a coordinated systemic allostatic response to chronic energy excess aimed at preserving metabolic homeostasis. Therapeutic success may depend not only on lowering glycemia but also on how interventions alter tissue-specific glucose handling and metabolic stress.