Response to Comment on Rickels et al. Loss-of-Function Mutations in ABCA1 and Enhanced β-Cell Secretory Capacity in Young Adults. Diabetes 2015;64:193–199

We thank Patankar et al. (1) for their comments on our article that reported enhanced β-cell secretory capacity in young adult carriers of ABCA1 mutations published recently in Diabetes (2). We read with interest their description of unpublished data that isolated mouse islets exhibit a dose-dependent relationship between islet cholesterol concentration and insulin secretion that changes direction once a concentration threshold is reached. These results highlight the importance of cellular cholesterol homeostasis for β-cell function and support our hypothesis that ABCA1 deficiency in young adults may result in changes in β-cell cholesterol content that augment the capacity for insulin secretion under conditions of increased secretory demand. The existence of a threshold beyond which further accumulation of cellular cholesterol is detrimental for insulin secretion is also consistent with the data reported by Vergeer et al. (3) and with our proposal of an interaction between advancing age and further accumulation of intracellular cholesterol eventually predisposing to islet dysfunction. We agree that further studies are needed that assess insulin secretion across a range of ages in carriers of ABCA1 mutations, as well as in patients in which LDL receptor activity is either lacking (as in patients with familial hypercholesterolemia) or upregulated (as during treatment with statins).

We disagree with the authors’ assessment that the choice to assess β-cell secretory capacity using the glucose-potentiated arginine test may have masked measurable differences in islet function. While such a statement could be made for arginine-induced insulin secretion under fasting conditions, glucose-potentiation of arginine-induced insulin secretion provides the most sensitive measure of β-cell secretory capacity as demonstrated by human models of pancreatic islet reduction (4) and transplantation (5). Indeed, we saw no difference in the acute insulin response to arginine between ABCA1 mutation carriers and control subjects at fasting glucose concentrations, yet significantly increased responses under hyperglycemic clamp conditions that are necessary to demonstrate the reserve capacity for insulin release. Of note, the results obtained with the glucose-potentiated arginine test were concordant with those obtained using a frequently sampled intravenous glucose tolerance test in a subgroup of subjects (see Supplementary Data in Rickels et al. [2]). In particular, we observed entirely normal first-phase insulin release to glucose in our younger ABCA1 mutation carriers, contrary to the decreased responses in older ABCA1 mutation carriers reported by the authors (3).