We thank the editor for allowing us to clarify an aspect of our recent article (1) in response to Liu et al. (2). We and others (3) found that KsJ mice resist excessive weight gain on a high-fat (HF) diet. There are well-known strain differences in this response. Nevertheless, epididymal fat pad mass and fed plasma nonesterified fatty acid levels were increased by HF in both genotypes (Table 1 in ref. 1). We did not claim obesity or diabetes. We agree that β-cell dysfunction was subclinical by basic measures after 12 weeks’ exposure (Table 1 in ref. 1).
Importantly, insulin secretion was reduced in HF-fed KsJ mice when they were challenged with glucose in vivo 15–120 min (Fig. 2A vs. 2B in ref. 1). Our original submission showed the control and HF-diet data within each genotype together, but the figure was modified in review. While insulin area under the curve was similar over the whole glucose challenge (Fig. 2C in ref. 1), it was significantly lower in the second phase (15–120 min: KsJ HF diet, 155.4 ± 24.52 vs. KsJ control diet, 239.4 ± 20.60; P < 0.05, n = 6). In vitro insulin secretion from islets of HF-fed KsJ mice showed a trend for suppressed glucose-stimulated insulin secretion (Fig. 3E in ref. 1). There were fewer islets in the HF-fed KsJ mice due to β-cell loss (which follows failure) (Fig. 3A–C in ref. 1), and we chose size-matched islets to better compare the secretory profile with our transgenics. Thus, Fig. 3E in ref. 1 effectively overestimates the secretory capacity of HF-fed KsJ mice by selecting their “healthy” surviving islets. Overall we concluded that there was β-cell failure in HF-fed KsJ mice.
The positive message is that β-cell–specific 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) overexpression unexpectedly augments glucose-stimulated insulin secretion against a lipotoxic challenge. Modest β-cell 11β-HSD1 elevation resembled the pattern found in mice that robustly compensate on HF diet. Going over this optimal threshold (homozygotes) compromised β-cell function, as found in genetically diabetic mice. As much as we would prefer simplistic linear answers to our research questions, the data are compatible with a U-shaped response.
Liu et al. (2) are incorrect in their assertion that glucocorticoids are purely suppressive of β-cell function—we provided a list of published data that evidenced both positive and negative effects. We offered plausible explanations for the discrepancies.
No potential conflicts of interest relevant to this article were reported.