We thank Taegtmeyer et al. (1) and Zaccardi et al. (2) for their insightful comments on our recent article (3). Both are very supportive of our view that insulin resistance (IR) has a protective role against insulin-mediated metabolic stress in overweight and obese patients with type 2 diabetes (T2D).
Our article is similar to several recent articles (4–7). With this consolidation of views, clinicians should consider the implications of this concept for their patients with obesity-associated T2D, as overriding IR could cause harm for critical tissues such as the heart. We entirely agree with Taegtmeyer et al. (1) that “in the management of diabetes of patients with heart failure the target should be the source [off-loading nutrients] rather than the destination of excess fuel [by overriding IR].”
Zaccardi et al. (2) ask, “Is β-cell failure a defense mechanism in IR subjects, too?” This is an excellent question we have also considered. In situations of chronic overnutrition, a person can either store excess energy safely in adipose tissue, or when adipose dysfunction develops as a consequence of adipose inflammation and oxidative and endoplasmic reticulum stress, excess fuel becomes available for ectopic deposition in other tissues where they can cause harm. One protection from this harm is the development of IR in these tissues (3). Another potential protection is the failure to secrete enough insulin due to β-cell dysfunction, which together with IR, would prevent against ectopic buildup of nutrients in critical tissues, but at the cost of T2D. Thus, β-cell dysfunction and hyperglycemia could trade one adverse outcome of diabetes for another, reducing short-term cardiovascular disease for an increased risk of longer-term microvascular disease.
Evidence is accumulating that β-cell failure in obesity-linked T2D is partially genetically determined and important in the pathophysiology of this disease (7,8); yet the possibility should be considered that some parts of the β-cell dysfunction in these patients are adaptive physiological defense responses. As well as protecting other tissues, these islet β-cell responses could be autoprotective against severe depletion of insulin stores and/or β-cell death caused by overstimulation of secretion to match IR. We previously proposed that the β-cell can gluco- and lipo-detoxify via enhanced glycerolipid–fatty acid cycling and increased fatty acid oxidation with the consequence of reduced function (7). Islet β-cell dedifferentiation may also be a protective mechanism for islet survival at the expense of function (9). Thus, in settings of chronic nutrient excess, β-cells may respond with processes that impair insulin secretion, the price they have to pay for the prevention of β-cell death and rapid progression to more severe diabetes (7). The hyperglycemia as a result of β-cell dysfunction may be the price the whole organism has to pay for survival.
Finally, IR and β-cell dysfunction, if providing defense in obesity-associated T2D, are doing this because of chronic fuel excess. Therefore, approaches to the management of these patients should include reduction in excess fuel supply and nutrient off-loading.
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Duality of Interest. C.J.N. has received speaking fees from AstraZeneca, Novartis, Takeda, and Merck Sharp & Dohme and has been a member of an advisory board for Sanofi. S.E.K. has been a member of advisory boards for Boehringer Ingelheim, Elcelyx, Genentech, GlaxoSmithKline, Intarcia, Janssen, Merck Sharp & Dohme, Novo Nordisk, Receptos, and Takeda. O.P. holds shares in Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.
