In their recent commentary discussing insulin hypersecretion, Mittendorfer et al. (1) presented two hypotheses in Fig. 2. In one, it is postulated that obesity-related insulin resistance could be due to primary increased insulin secretion. This would occur because increased insulin concentrations would lead to decreased numbers of surface insulin receptors (due to intracellular translocation of the bound receptors after binding to insulin). However, only a minority of insulin receptors need to bind insulin for maximal action in insulin-sensitive tissues. In vitro measurements of insulin binding and dose responses of insulin action in insulin-sensitive tissues revealed that in adipocytes only 2–10%, in soleus muscle only 20%, and in hepatocytes only 35% of insulin receptors need to bind insulin to yield a maximal effect (2). This means that between 65% and 90% of insulin receptors in these tissues were spare, i.e., did not need to be bound by insulin for the hormone’s maximal effect. The alternative hypothesis in Fig. 2, which has been promulgated for many years, describes increased adipose tissue, i.e., obesity, yielding increased circulating nonesterified fatty acids that cause insulin resistance (3,4), which in turn leads to increased insulin secretion. To the extent that the in vitro demonstration of the large number of spare receptors on insulin-sensitive tissues is valid in vivo, this largely unappreciated phenomenon should be considered and speaks against primary increased insulin secretion and favors secondary increased insulin secretion in response to insulin resistance. As is most often the case, further studies are necessary to determine which of these two hypotheses is more valid.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

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