Insulin Resistance as a Physiological Defense Against Metabolic Stress: Implications for the Management of Subsets of Type 2 Diabetes

Abstract

Stratifying the management of type 2 diabetes (T2D) has to take into account marked variability in patient phenotype due to heterogeneity in its pathophysiology, different stages of the disease process, and multiple other patient factors including comorbidities. The focus here is on the very challenging subgroup of patients with T2D who are overweight or obese with insulin resistance (IR) and the most refractory hyperglycemia due to an inability to change lifestyle to reverse positive energy balance. For this subgroup of patients with T2D, we question the dogma that IR is primarily harmful to the body and should be counteracted at any cost. Instead we propose that IR, particularly in this high-risk subgroup, is a defense mechanism that protects critical tissues of the cardiovascular system from nutrient-induced injury. Overriding IR in an effort to lower plasma glucose levels, particularly with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of “IR as an adaptive defense mechanism” and “insulin-induced metabolic stress” may provide explanation for some of the unexpected outcomes of recent major clinical trials in T2D. Potential molecular mechanisms underlying these concepts; their clinical implications for stratification of T2D management, particularly in overweight and obese patients with difficult glycemic control; and future research requirements are discussed.

Insulinresistens – kroppens forsvar mot kaloriforgiftning?

“…Nye hypoteser om patogenesen til type 2-diabetes er blitt lansert de siste årene og kan bidra til å kaste nytt lys over hvorfor resultatene med intensiv glykemisk kontroll i studier har vaert lite oppløftende (12,13).…”

“…En hypotese er derfor at kardiomyocyttene induserer insulinresistens for å beskytte seg mot dette fatale utfallet (12,13). Ulike grader av insulinresistens kan induseres på tilsvarende måte i lever, fettvev og skjelettmuskulatur.…”

“…Når kroppen når sin maksimale lagringskapasitet, er også taket nådd for insulinresistens, og ytterligere betacellekompensasjon med økt insulinproduksjon er nytteløst. Videre hyperinsulinemi kan da vaere skadelig, eksempelvis for hjertemuskulatur fordi den blir gjenstand for metabolsk overbelastning (12,13). Sett i lys av dette er det nylig blitt foreslått at «betacellesvikt» i seg selv også kan vaere en adaptiv fysiologisk forsvarsmekanisme, hvor betacellene ikke nødvendigvis kollapser som følge av overarbeid, men reduserer sin insulinproduksjon aktivt for å beskytte vitale organer og seg selv mot overeksponering av insulin (20).…”

“…Overstyring av insulinresistens hos slike pasienter kan presse mer energi inn i hjertemuskulatur som allerede lider under metabolsk stress (12,13). ACCORD-studien ble stoppet tidlig på grunn av økt mortalitet i gruppen som fikk intensiv glykemisk behandling (10).…”

Prevalence of Anxiety and Depression in Diabetic Patients: A Comparative Study

“…In this disease the body's ability to produce insulin is lost or the body becomes resistant to insulin, so the produced insulin cannot perform its normal function (1,2). According to the statistics provided by the world health organization, 285 million people suffer from diabetes worldwide and this amount will reach 438 million per year by 2030 (3)(4)(5).…”