title: 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.
authors.affiliation: Department of Endocrinology at Canberra Hospital and the Australian National University Medical School, Canberra, Australia christopher.nolan@anu.edu.au.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nolan
authors.affiliation: Diabetes Research Unit, Boston University Medical Center, Boston, MA.
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ruderman
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System, and University of Washington, Seattle, WA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: CRCHUM and Montreal Diabetes Research Center and Departments of Nutrition and Biochemistry and Molecular Medicine, University of Montreal, Quebec, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D007328:Insulin / Q000009:adverse effects / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology*; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin