We read with great interest the recent article by Nolan et al. (1) in which the authors, summarizing previous basic and pathophysiological research, propose the concept of insulin resistance (IR) as a protective mechanism in overweight/obese subjects with type 2 diabetes. As a consequence of this premise, they argue against intensive insulin treatment as an approach to override IR with the final goal of satisfactory blood glucose control in obese subjects unlikely to correct positive energy balance through lifestyle interventions (1).
While congratulating them for this important point of view that further underlines the need for a “personalized” medical approach to type 2 diabetes phenotypes, we believe that an additional consequence could be derived from their considerations: is β-cell failure a defense mechanism in IR subjects, too?
It is well recognized and accepted that in type 2 diabetes hyperglycemia develops when β-cells cannot cope with the increasing insulin demand to maintain euglycemia because of IR (2). If the premise of harmful effects of hyperinsulinemia is correct, β-cell failure in overweight/obese subjects would be a mechanism to protect organs and tissues from overexposure to insulin and its potential negative long-term effects (1). At the same time, lack of insulin, the consequent glycosuria, and β-oxidation “shift” of metabolism would eventually result, at least theoretically, in restoring insulin sensitivity. While β-cell failure would preserve some tissue from being overexposed to insulin, it would also result in glucose-mediated damages to the nerves, eye, and kidney, leaving the clinician to face a trade-off (1).
Notwithstanding all these considerations, we certainly believe that the reflections of Nolan et al. (1) further emphasize that the simple, historical, and etymological “glucocentric” approach of diabetes should be reconsidered (3), particularly when it is viewed in light of its relationship with not only microvascular and macrovascular complications but also nonvascular complications (4,5).
Article Information
Funding. The authors acknowledge the support of the following institutes for this work: the National Institute for Health Research, Collaboration for Leadership in Applied Health Research and Care–East Midlands (NIHR CLAHRC East Midlands) and the NIHR Diet, Lifestyle and Physical Activity Biomedical Research Unit based at University Hospitals of Leicester and Loughborough Universities. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health.
Duality of Interest. F.Z. is a clinical research fellow funded by Sanofi. K.K. has acted as a consultant and speaker for Novartis, Novo Nordisk, Sanofi, Lilly, and Merck Sharp & Dohme. He has received grants in support of investigator and investigator-initiated trials from Novartis, Novo Nordisk, Sanofi, Lilly, Pfizer, Boehringer Ingelheim, and Merck Sharp & Dohme. He has received funds for research and honoraria for speaking at meetings and has served on advisory boards for Lilly, Sanofi, Merck Sharp & Dohme, and Novo Nordisk. M.J.D. has acted as a consultant, advisory board member, and speaker for Novo Nordisk, Sanofi, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Janssen and as a speaker for Mitsubishi Tanabe Pharma Corp. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi, and Lilly. No other potential conflicts of interest relevant to this article were reported.
